U.S. patent number 8,367,843 [Application Number 13/499,190] was granted by the patent office on 2013-02-05 for phenol derivative.
This patent grant is currently assigned to Fuji Yakuhin Co., Ltd.. The grantee listed for this patent is Naoki Ashizawa, Tsutomu Inoue, Takashi Iwanaga, Seiichi Kobashi, Koji Matsumoto, Sachiho Miyata, Osamu Nagata, Tetsuya Taniguchi, Junichiro Uda. Invention is credited to Naoki Ashizawa, Tsutomu Inoue, Takashi Iwanaga, Seiichi Kobashi, Koji Matsumoto, Sachiho Miyata, Osamu Nagata, Tetsuya Taniguchi, Junichiro Uda.
United States Patent |
8,367,843 |
Kobashi , et al. |
February 5, 2013 |
**Please see images for:
( Certificate of Correction ) ** |
Phenol derivative
Abstract
Disclosed are a novel compound and a pharmaceutical product,
each having a remarkable uricosuric effect. Specifically disclosed
are: a novel phenol derivative represented by general formula (1)
that is shown in FIG. 1; a pharmaceutically acceptable salt
thereof; a hydrate of the derivative or the salt; and a solvate of
the derivative or the salt. (In the formula, R.sup.1 and R.sup.2
may be the same or different and each represents a lower alkyl
group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy
group, a haloalkyl group, a haloalkoxy group, an alkylsulfanyl
group, an alkylsulfinyl group, an alkylsulfonyl group, a lower
alkyl-substituted carbamoyl group, a saturated nitrogen-containing
heterocyclic N-carbonyl group, a halogen atom, a cyano group or a
hydrogen atom; R.sup.3 represents a lower alkyl group, a haloalkyl
group, a halogen atom, a hydroxy group or a hydrogen atom; and X
represents a sulfur atom, an --S(.dbd.O)-- group or an
--S(.dbd.O).sub.2-- group.)
Inventors: |
Kobashi; Seiichi (Saitama,
JP), Uda; Junichiro (Saitama, JP), Miyata;
Sachiho (Saitama, JP), Inoue; Tsutomu (Saitama,
JP), Ashizawa; Naoki (Saitama, JP),
Matsumoto; Koji (Saitama, JP), Taniguchi; Tetsuya
(Saitama, JP), Iwanaga; Takashi (Saitama,
JP), Nagata; Osamu (Saitama, JP) |
Applicant: |
Name |
City |
State |
Country |
Type |
Kobashi; Seiichi
Uda; Junichiro
Miyata; Sachiho
Inoue; Tsutomu
Ashizawa; Naoki
Matsumoto; Koji
Taniguchi; Tetsuya
Iwanaga; Takashi
Nagata; Osamu |
Saitama
Saitama
Saitama
Saitama
Saitama
Saitama
Saitama
Saitama
Saitama |
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A |
JP
JP
JP
JP
JP
JP
JP
JP
JP |
|
|
Assignee: |
Fuji Yakuhin Co., Ltd.
(Saitama, JP)
|
Family
ID: |
43826265 |
Appl.
No.: |
13/499,190 |
Filed: |
September 29, 2010 |
PCT
Filed: |
September 29, 2010 |
PCT No.: |
PCT/JP2010/066925 |
371(c)(1),(2),(4) Date: |
March 29, 2012 |
PCT
Pub. No.: |
WO2011/040449 |
PCT
Pub. Date: |
April 07, 2011 |
Prior Publication Data
|
|
|
|
Document
Identifier |
Publication Date |
|
US 20120184587 A1 |
Jul 19, 2012 |
|
Foreign Application Priority Data
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|
|
|
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Sep 30, 2009 [JP] |
|
|
2009-227402 |
|
Current U.S.
Class: |
548/180 |
Current CPC
Class: |
A61P
7/02 (20180101); A61P 19/02 (20180101); A61P
9/12 (20180101); A61P 13/12 (20180101); A61P
19/06 (20180101); A61P 9/00 (20180101); A61P
3/06 (20180101); C07D 417/10 (20130101); A61P
7/00 (20180101); A61P 9/10 (20180101); C07D
417/02 (20130101); A61P 3/04 (20180101); A61P
13/04 (20180101); A61P 3/10 (20180101); C07D
277/62 (20130101) |
Current International
Class: |
A61K
31/428 (20060101); C07D 277/62 (20060101) |
Field of
Search: |
;548/180 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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WO 2006/057460 |
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Jun 2006 |
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WO |
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WO 2007/138998 |
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Dec 2007 |
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WO |
|
Other References
Colagiuri et al., American Journal of Public Health, Sep. 2006,
vol. 96, No. 9, pp. 1562-1569. cited by examiner .
Bruno et al., Expert Opinion Emerging Drugs, (2005), 10(4), pp.
747-771. cited by examiner .
Park, Diabetes Research and Clinical Practice 66S (2004), S33-S35.
cited by examiner .
Curtis et al., The Journal of the American Board of Family
Practice, vol. 18, pp. 37-43, (2005). cited by examiner .
Guidelines for the Management of Hyperuricemia and Gout (First
Edition), Gout and Nucleic Acid Metabolism, Japanese Society of
Gout and Nucleic Acid Metabolism, vol. 26, Supplement 1, 2002, pp.
7-9 and pp. 30-33. cited by applicant .
Fang et al., Serum Uric Acid and Cardiovascular Mortality, JAMA,
May 10, 2000, vol. 283, No. 18, pp. 2404-2410. cited by applicant
.
Bos et al., Uric Acid is a Risk Factor for Myocardial Infarction
and Stroke: The Rotterdam Study, Stroke, Journal of the American
Heart Association, downloaded from http://stroke.ahajournals.org/,
Aug. 29, 2012, pp. 1503-1507. cited by applicant .
Kanellis et al., Does asymptomatic hyperuricaemia contribute to the
development of renal and cardiovascular disease? An old controversy
renewed, Nephrology, 2004, 9, pp. 394-399. cited by applicant .
Kang et al., Uric Acid and Chronic Renal Disease: Possible
Implication of Hyperuricemia on Progression of Renal Disease, WBS,
Seminars in Nephrology, 2005, pp. 43-49. cited by applicant .
Viazzi et al., Serum Uric Acid as a Risk Factor for Cardiovascular
and Renal Disease: An Old Controversy Revived, The Journal of
Clinical Hypertension, vol. 8, No. 7, Jul. 2006, pp. 510-518. cited
by applicant .
Puig et al., Uric acid as a cardiovascular risk factor in arterial
hypertension, Journal of Hypertension, 1999, 17, pp. 869-872. cited
by applicant .
Alderman et al., Uric acid: role in cardiovascular disease and
effects of losartan, Current Medical Research and Opinion, vol. 20,
No. 3, 2004, pp. 369-379. cited by applicant .
Schachter, Uric Acid and Hypertension, Current Pharmaceutical
Design, 2005, 11, Bentham Science Publishers Ltd., pp. 4139-4143.
cited by applicant .
Viazzi et al., Serum Uric Acid and Target Organ Damage in Primary
Hypertension, downloaded from hyper.ahajournals.org, Jul. 29, 2009,
pp. 991-996. cited by applicant .
Hsu et al., Risk Factors for End-Stage Renal Disease, Arch Intern
Med., vol. 169, No. 4, Feb. 23, 2009, pp. 342-350. cited by
applicant .
Tohgi et al., The urate and xanthine concentrations in the
cerebrospinal fluid in patients with vascular dementia of the
Binswanger type, Alzheimer type dementia, and Parkinson's disease,
Journal of Neural Transmission, 6, 1993, pp. 119-126. cited by
applicant .
Siu et al., Use of Allopurinol in Slowing the Progression of Renal
Disease Through its Ability to Lower Serum Uric Acid Level,
American Journal of Kidney Diseases, vol. 47, No. 1, Jan. 2006, pp.
51-59. cited by applicant .
Hyperuricaemia and Gout, vol. 9, No. 1, 2001, pp. 61-65. cited by
applicant .
Nakamura et al., Dynamics of uric acid metabolism in hyperuricemia,
Internal Medicine I, Fukui Medical School, pp. 3230-3236, 1996.
cited by applicant .
Nakamura et al., Characteristic features of gouty patients,
Department of Medicine, Fukui Medical School, pp. 3248-3255, 1996.
cited by applicant .
Van Der Klauw et al., Hepatic injury caused by benzbromarone,
Journal of Hepatology, 1994, 20, pp. 376-379. cited by applicant
.
Spaniol et al., Toxicity of amiodarone and amiodarone analogues on
isolated rat liver mitochondria, Journal of Hepatology, 35, 2001,
pp. 628-636. cited by applicant .
Kaufmann et al., Mechanisms of Benzarone and Benzbromarone-Induced
Hepatic Toxicity, Hepatology, vol. 41, No. 4, 2005, pp. 925-935.
cited by applicant .
Kunishima et al., Benzbromarone (Urinorm), Fourth Deparment of
Internal Medicine, Medical School, The Medical Society of Saitama
Medical School, 2003, pp. 187-194. cited by applicant .
Locuson II et al., A New Class of CYP2C9 Inhibitors: Probing 2C9
Specificity with High-Affinity Benzbromarone Derivatives, Drug
Metabolism and Disposition, vol. 31, No. 7, 2003, pp. 967-971.
cited by applicant .
Proceedings of the 42nd Annual Meeting of the Japanese Society of
Gout and Nucleic Acid Metabolism, 2009, p. 59. cited by applicant
.
ACR 2008 Annual Scientific Meeting, No. 28, p. 1. cited by
applicant.
|
Primary Examiner: Stockton; Laura L.
Attorney, Agent or Firm: Price Heneveld LLP
Claims
The invention claimed is:
1. A phenol derivative represented by the following formula (1)
##STR00012## wherein R.sup.1 and R.sup.2 are the same or different
and represent a lower alkyl group, a lower alkenyl group, a lower
alkynyl group, a lower alkoxy group, a haloalkyl group, a
haloalkoxy group, an alkylsulfanyl group, an alkylsulfinyl group,
an alkylsulfonyl group, a lower alkyl-substituted carbamoyl group,
a saturated nitrogen-containing heterocyclic N-carbonyl group, a
halogen atom, a cyano group or a hydrogen atom, R.sup.3 represents
a lower alkyl group, a haloalkyl group, a halogen atom, a hydroxyl
group or a hydrogen atom, and X represents a sulfur atom,
--S(.dbd.O)-- or --S(.dbd.O).sub.2--, a pharmaceutically acceptable
salt thereof, a hydrate thereof or a solvate thereof.
2. The compound according to claim 1, wherein R.sup.1 represents a
lower alkyl group, a lower alkenyl group, a lower alkynyl group, a
lower alkoxy group, a haloalkyl group, a haloalkoxy group, an
alkylsulfanyl group, a lower alkyl-substituted carbamoyl group, a
saturated nitrogen-containing heterocyclic N-carbonyl group or a
halogen atom, R.sup.2 represents a cyano group, a haloalkyl group
or a halogen atom, R.sup.3 represents a haloalkyl group, a hydroxyl
group or a hydrogen atom, and X represents a sulfur atom or
--S(.dbd.O).sub.2--, a pharmaceutically acceptable salt thereof, a
hydrate thereof or a solvate thereof.
3. The compound according to claim 1, wherein R.sup.1 represents a
haloalkyl group or a halogen atom, R.sup.2 represents a cyano group
or a halogen atom, R.sup.3 represents a hydrogen atom, and X
represents --S(.dbd.O).sub.2--, a pharmaceutically acceptable salt
thereof, and a hydrate thereof and a solvate thereof.
4. A pharmaceutical composition comprising, as an active
ingredient, one or more substances selected from the group
consisting of the compound according to claim 1, a pharmaceutically
acceptable salt thereof, a hydrate thereof, and a solvate
thereof.
5. The pharmaceutical composition on according to claim 4 which is
in the form of a pharmaceutical composition containing one, or two,
or more additives for formulation.
6. A method of acceleration of excretion of uric acid, comprising
the step of administering the pharmaceutical composition of claim 5
to a patient.
7. A method of acceleration of excretion of uric acid, comprising
the step of administering the pharmaceutical composition of claim 4
to a patient.
8. A method of reducing uric acid in blood or tissue comprising the
step of administering the pharmaceutical composition of claim 4 to
a patient.
9. A method of reducing uric acid in blood or tissue comprising the
step of administering the pharmaceutical composition of claim 5 to
a patient.
10. A method for or treating hyperuricaemia comprising the step of
administering the pharmaceutical composition of claim 4 to a
patient.
11. A method for or treating hyperuricaemia comprising the step of
administering the pharmaceutical composition of claim 5 to a
patient.
12. A pharmaceutical composition comprising, as an active
ingredient, one or more substances selected from the group
consisting of the compound according to claim 2, a pharmaceutically
acceptable salt thereof, a hydrate thereof, and a solvate
thereof.
13. A pharmaceutical composition comprising, as an active
ingredient, one or more substances selected from the group
consisting of the compound according to claim 3, a pharmaceutically
acceptable salt thereof, a hydrate thereof, and a solvate thereof.
Description
TECHNICAL FIELD
The present invention relates to a novel phenol derivative which
exhibits high concentration of an unchanged compound in urine, and
also has a remarkable uricosuric action, or a pharmaceutically
acceptable salt thereof, or a hydrate thereof or a solvate thereof,
and a pharmaceutical containing the same as an active
ingredient.
BACKGROUND ART
Uric acid is generated by catabolizing purine, which is formed by
decomposition of nucleic acid and adenosine triphosphate (ATP)
which is an energy source of the living body, and then by oxidizing
the metabolized purine, xanthine, by xanthineoxidase or
xanthinedehydrogenase. In case of humans, uric acid (dissociation
constant pKa=5.75) is a final metabolite of purine, and is present
in the body as a free uric acid or salt.
Uric acid is usually excreted in urine, and hyperuricaemia is
caused when uric acid production exceeds its excretion and uric
acid in blood is increased. When an excess of uric acid level in
blood over upper limit (about 7 mg/dL) of solubility continues for
a long period, a crystal of a urate (usually sodium salt) is
precipitated.
Urate crystal is deposited on cartilaginous tissues or joints to
form a precipitate, and thus leading to gouty node. Whereby, acute
gouty arthritis is caused and evolved to chronic gouty
arthritis.
When the crystal of the urate is precipitated in urine, renal
damage (gouty kidney) such as interstitial nephritis, urinary stone
and the like are created. After calming down of stroke of acute
gouty arthritis, pharmacotherapy is performed together with the
life style improvement support so as to correct hyperuricaemia.
It is important to correct hyperuricaemia and to appropriately
manage a uric acid value so as to prevent acute gouty arthritism,
gouty kidney, urinary stone and the like.
It is considered that hyperuricaemia is complicated by
lifestyle-related diseases such as obesity, hyperlipemia, abnormal
glucose tolerance and hypertension at a high rate (see Non-Patent
Literature 1 (pp 7-9)). An increase in serum urate concentration
exhibits a positive relationship with a death rate due to
cardiovascular diseases. Since high serum urate concentration
increases death due to cardiovascular diseases, it is suggested
that an increase in serum uric acid level is singly and
significantly involved in a risk of death due to cardiovascular
diseases, (see Non-Patent Literature 2).
It is also suggested that the serum urate concentration is a strong
risk factor of myocardial infarction and cerebral haemorrhage (see
Non-Patent Literature 3). It has been reported until now that
hyperuricaemia is associated with obesity, hyperlipemia,
dyslipidemia, abnormal glucose tolerance, diabetes, metabolic
syndrome, renal disease (for example, renal insufficiency, urine
protein, end stage kidney disease (ESRD), etc.), cardiovascular
diseases (for example, hypertension, coronary artery disease,
carotid artery disease, endothelial dysfunction, arteriosclerosis,
cardiac hypertrophy, cerebrovascular disease, etc.) or a risk
factor of these diseases (see Non-Patent Literatures 2 to 11). It
has also been reported that the concentration of uric acid in the
cerebrospinant increases in vascular dementia (see Non-Patent
Literature 12).
Under these circumstances, it is suggested that decrease in blood
urate level can delay the proceeding of renal disease, and also can
reduce a risk of cardiovascular disease (see Non-Patent Literatures
5, 8, 13 and 14), and it is reported that the treatment should also
be applied to asymptomatic hyperuricaemia (see Non-Patent
Literature 14).
Accordingly, it is considered that a decrease in blood urate level
in the above-mentioned diseases is effective for the treatment or
prevention of these diseases, and is also important from the
viewpoint of preventing the recurrence of cardiovascular accident
and maintaining a renal function.
The main factor of an increase in blood urate level include
overproduction and underexcretion of uric acid. It is considered
that a method for suppression of the production of uric acid or
acceleration of excretion of uric acid is effective as a method for
decreasing a blood urate level. It is known that a drug (uric acid
production inhibitor) having a mechanism of action of the former
includes allopurinol, while a drug (uricosuric drug) having a
mechanism of action of the latter includes benzbromarone,
probenecid, JP-A-2006-176505 (Patent Literature 1) or the like.
Japanese guidelines for the management of hyperuricemia and gout
describes that, in case of a treatment of hyperuricaemia, a
uricosuric drug is applied for patients with underexcretion of uric
acid and a uric acid production inhibitor is applied against
patients with overproduction of uric acid, respectively, as a
general Hide (see Non-Patent Literature 1 (pp. 31-32)).
It is said in Japan that patients with underexcretion of uric acid
account for about 60% of hyperuricaemia patients and mix type
patients with both underexcretion and overproduction of uric acid
account for about 25% of hyperuricaemia patients (Non-Patent
Literature 15). It is also reported that underexcretion of uric
acid is observed in about 85% of gout patients, and even in
patients with overproduction of uric acid, an average of uric acid
clearance is significantly lower than that of a healthy person, and
underexcretion of uric acid as a common phenomenon in all gout
patients is suggested (Non-Patent Literature 16).
Accordingly, treatment for patients with underexcretion of uric
acid is considered to be important in hyperuricaemia (particularly
gout) and significance of the existence of a uricosuric drug is
remarkably great.
Among main uricosuric drugs, probenecid is scarcely used since it
has a weak action, and gastrointestinal disturbance and an
interaction with other drugs are recognized, while serious liver
damage is reported in benzbromarone which has a strong uricosuric
action and is popularly used as a uricosuric drug in Japan (see
Non-Patent Literature 17).
Benzbromarone or an analog thereof exhibits mitochondria toxicity,
for example, inhibition of enzyme complex activity of a respiratory
chain of mitochondria, uncoupling action, inhibition of
respiration, inhibition of fatty acid .beta. oxidation, reduction
in mitochondria membrane potential, apoptosis, production of
reactive oxygen species and the like, and it is suggested that
mitochondria toxicity is involved in the onset of liver damage (see
Non-Patent Literatures 18 and 19). An active metabolite of
benzbromarone, 6-hydroxy benzbromarone also exhibits toxicity
against mitochondria.
Furthermore, benzbromarone has an action of inhibiting cytochrome
P450 (CYP) which is a drug metabolizing enzyme and reveals
particularly strong inhibition against CYP2C9, and it is suggested
to cause a pharmacokinetic drug interaction (see Non-Patent
Literatures 20 and 21).
JP-A-2006-176505 (Patent Literature 1) describes a
nitrogen-containing fused ring compound, which has an inhibitory
action on URAT1 as a kind of urate transporters and also has a
structure analogous to that of the compounds of the present
invention. However, the compound does not have a sufficient effect
and a practicable novel uricosuric drug has not been developed
yet.
There has recently been obtained a finding that an uricosuric
action depends on the concentration of a drug having the same
action in urine, that is, a uricosuric drug exhibits drug
effectiveness by being excreted in urine (see Patent Literature 2,
Non-Patent Literatures 22 and 23).
Accordingly, more potent, effective uricosuric drug which is
excreted in urine in larger quantities is expected. However, the
above existing uricosuric drug shows drastically low concentration
in urine, and it cannot be said that satisfactory activity is
obtained.
With respect to excretion of the drug in urine, the case where the
administered drug is excreted as an unchanged compound as it is,
and the case where the drug is converted into an active metabolite
and then excreted can be estimated. In the latter case, there is a
risk that an individual difference in production amount of the
active metabolite may increase. In order to obtain stable drug
effectiveness and safety, a drug to be excreted as an unchanged
compound is more desirable.
[So, it is desired to develop a pharmaceutical which exhibits a
high concentration of an unchanged compound in urine, and also has
a remarkable uricosuric action and high safety as compared with an
existing uricosuric drug.
CITATION LIST
Patent Literature
Patent Literature 1: JP-A-2006-176505 Patent Literature 2: WO
2005/121112
Non-Patent Literatures
Non-Patent Literature 1: Guidelines for the Management of
Hyperuricemia and Gout (First Edition) pp. 7-9, and pp. 31-32, Gout
and Nucleic Acid Metabolism, Vol. 26, Supplement 1, 2002, Japanese
Society of Gout and Nucleic Acid Metabolism Non-Patent Literature
2: JAMA 283: 2404-2410 (2000) Non-Patent Literature 3: Stroke 37:
1503-1507 (2006) Non-Patent Literature 4: Nephrology 9: 394-399
(2004) Non-Patent Literature 5: Semin. Nephrol. 25: 43-49 (2005)
Non-Patent Literature 6: J. Clin. Hypertens. 8: 510-518 (2006)
Non-Patent Literature 7: J. Hypertens. 17: 869-872 (1999)
Non-Patent Literature 8: Curr. Med. Res. Opin. 20: 369-379 (2004)
Non-Patent Literature 9: Curr. Pharm. Des. 11: 4139-4143 (2005)
Non-Patent Literature 10: Hypertension 45: 991-996 (2005)
Non-Patent Literature 11: Arch. Intern. Med. 169: 342-350 (2009)
Non-Patent Literature 12: J. Neural. Transm. Park Dis. Dement.
Sect. 6: 119-126 (1993) Non-Patent Literature 13: Am. J. Kidney
Dis. 47:51-59 (2006) Non-Patent Literature 14: Hyperuricaemia and
Gout 9: 61-65 (2001) Non-Patent Literature 15: Nippon Rinsho 54:
3230-3236 (1996) Non-Patent Literature 16: Nippon Rinsho 54:
3248-3255 (1996) Non-Patent Literature 17: J. Hepatol. 20: 376-379
(1994) Non-Patent Literature 18: J. HepatoL 35: 628-636 (2001)
Non-Patent Literature 19: Hepatology 41: 925-935 (2005) Non-Patent
Literature 20: Journal of Saitama Medical University (J. Saitama.
Med. School) 30: 187-194 (2003) Non-Patent Literature 21: Drug
Metab. Dispos. 31: 967-971 (2003) Non-Patent Literature 22:
Proceedings of the 42nd Annual Meeting of the Japanese Society of
Gout and Nucleic Acid Metabolism, p. 59 (2009) Non-Patent
Literature 23: ACR 2008 Annual Scientific Meeting, No. 28
SUMMARY OF INVENTION
Technical Problem
An object of the present invention is to provide novel compounds
and pharmaceutical, each having a remarkable uricosuric action.
Solution to Problem
The present inventors have intensively studied so as to achieve the
above object and found a novel phenol derivative having high safety
and a remarkable uricosuric action, and thus the present invention
has been completed.
That is, according to the present invention, there are provided a
novel phenol derivative represented by the following general
formula (1):
##STR00001## wherein R1 and R2 are the same or different and
represent a lower alkyl group, a lower alkenyl group, a lower
alkynyl group, a lower alkoxy group, a haloalkyl group, a
haloalkoxy group, an alkylsulfanyl group, an alkylsulfinyl group,
an alkylsulfonyl group, a lower alkyl-substituted carbamoyl group,
a saturated nitrogen-containing heterocyclic N-carbonyl group, a
halogen atom, a cyano group or a hydrogen atom, R3 represents a
lower alkyl group, a haloalkyl group, a halogen atom, a hydroxyl
group or a hydrogen atom, and X represents a sulfur atom, --S(O)--
or --S(O).sub.2--, a pharmaceutically acceptable salt thereof and a
hydrate thereof and a solvate thereof and a pharmaceutical
composition containing them.
In the present description, the "lower alkyl group" is a C1-6 alkyl
group, and may be any of linear, branched and cyclic lower alkyl
groups, and an alkyl group consisting of a combination thereof. The
same shall apply to alkyl moieties of the substituents having an
alkyl moiety [lower alkoxy group, lower alkyl-substituted carbamoyl
group, alkylsulfanyl group, etc.]. Examples of the C1-6 alkyl group
include a methyl group, an ethyl group, an n-propyl group, an
isopropyl group, an n-butyl group, an isobutyl group, an s-butyl
group, a t-butyl group, an n-pentyl group, an n-hexyl group, a
cyclopropyl group, a cyclobutyl group and the like. Examples of the
lower alkoxy group include a methoxy group, an ethoxy group, an
n-propoxy group, an isopropoxy group, a cyclopropoxy group, an
n-butoxy group, an isobutoxy group, a t-butoxy group, an n-pentoxy
group, an n-hexyloxy group and the like. Examples of the lower
haloalkoxy group include a trifluoromethoxy group and a
trifluoroethoxy group. Examples of the lower haloalkyl group
include a trifluoromethyl group, a trifluoroethyl group and the
like. Examples of the lower alkylsulfanyl group include a
methylsulfanyl group, an ethylsulfanyl group, an isopropylsulfanyl
group and the like. Examples of the halogen atom include a fluorine
atom, a chlorine atom, a bromine atom and an iodine atom. Examples
of the lower alkyl-substituted carbamoyl group include a
methylcarbamoyl group, an ethylcarbamoyl group, a dimethylcarbamoyl
group, a diethylcarbamoyl group and the like. Examples of the
saturated nitrogen-containing heterocyclic N-carbonyl group include
a pyrrolidin-1-ylcarbonyl group, a thiazolidin-3-ylcarbonyl group,
a 1-oxothiazolidin-3-ylcarbonyl group, a
1,1-dioxothiazolidin-3-ylcarbonyl group and the like. Examples of
the lower alkenyl group include a vinyl group, a propenyl group and
the like. Examples of the lower alkynyl group include an ethynyl
group, a propynyl group and the like. Examples of the lower
alkylsulfinyl group include a methylsulfinyl group, an
ethylsulfinyl group and the like. Examples of the lower
alkylsulfonyl group include a methylsulfonyl group, an
ethylsulfonyl group and the like.
The lower alkyl group represented by R1 is preferably an ethyl
group, an isopropyl group, an n-butyl group, a t-butyl group, a
cyclopropyl group or a cyclobutyl group. The lower haloalkyl group
is preferably a trifluoromethyl group. The lower alkoxy group is
preferably a methoxy group. The lower haloalkoxy group is
preferably a trifluoromethoxy group. The alkylsulfanyl group is
preferably a methylsulfanyl group, an ethylsulfanyl group or an
isopropylsulfanyl group. The alkylsulfonyl group is preferably a
methylsulfonyl group. The halogen atom is preferably a fluorine
atom or a chlorine atom. The lower alkyl-substituted carbamoyl
group is preferably a dimethylcarbamoyl group. The saturated
nitrogen-containing heterocyclic N-carbonyl group is preferably a
pyrrolidin-1-ylcarbonyl group, a thiazolidin-3-ylcarbonyl group, a
1-oxothiazolidin-3-ylcarbonyl group or a
1,1-dioxothiazolidin-3-ylcarbonyl group. The lower alkynyl group is
preferably an ethynyl group. The lower alkylsulfinyl group is
preferably a methylsulfinyl group. R2 is preferably a fluorine
atom, a chlorine atom, a cyano group, a methylsulfonyl group or a
trifluoromethyl group. X is preferably a sulfur atom or
--S(.dbd.O).sub.2--. R3 is preferably a hydroxyl group, a
trifluoromethyl group or a hydrogen atom.
More preferably, there can be exemplified compounds in which X is
--S(.dbd.O).sub.2--, R1 is a chlorine atom, a lower alkyl group, a
lower alkoxy group, a trifluoromethoxy group, an alkylsulfanyl
group or a trifluoromethyl group, R2 is a cyano group, a chlorine,
a fluorine atom, a methylsulfonyl group or a trifluoromethyl group,
and R3 is a hydrogen atom or a hydroxyl group.
Specifically, the compounds are preferably
3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole-
,
3-(3-chloro-5-cyano-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothi-
azole,
3-(3-cyano-4-hydroxy-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dihydr-
o-1,3-benzothiazole,
3-(3-cyano-5-ethyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiaz-
ole,
3-(3-cyano-4-hydroxy-5-methylsulfanylbenzoyl)-1,1-dioxo-2,3-dihydro-1-
,3-benzothiazole,
3-(3-cyano-5-ethylsulfanyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-be-
nzothiazole,
3-(3-chloro-4-hydroxy-5-methylsulfanylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3--
benzothiazole,
3-(3-chloro-4-hydroxy-5-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzoth-
iazole,
3-(3-chloro-5-fluoro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-b-
enzothiazole,
3-(3-chloro-4-hydroxy-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-
-benzothiazole,
3-(3-chloro-4-hydroxy-5-trifluoromethoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,-
3-benzothiazole,
3-(5-t-butyl-4-hydroxy-3-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-
-benzothiazole,
3-(3-cyano-5-cyclopropyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benz-
othiazole,
3-(3-cyano-5-ethynyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,-
3-benzothiazole or a pharmaceutically acceptable salt thereof, or a
hydrate thereof or a solvate thereof.
With respect to the compounds of the present invention, isomers may
exist. For example, geometric isomers, optical isomers or
diastereoisomers may exist. Any of single isomer of these isomers,
arbitrary mixtures of isomers, racemates and the like falls within
the scope of the present invention.
The compounds of the present invention may form a base addition
salt or an acid addition salt depending on a type of the
substituent. There is no particular limitation on a type of the
salt, and examples thereof include, but are not limited to, metal
salts such as sodium salts, potassium salts and calcium salts; base
addition salts such as ammonium salts and organic amine salts;
mineral acid salts such as hydrochlorides, sulfates and nitrates;
organic acid salts such as p-toluenesulfonates, methanesulfonates
and tartrates.
The compounds of the present invention and salts thereof may exist
as a hydrate or a solvate, and these substances also fall within
the scope of the present invention. Examples of the hydrate include
1/2 hydrates, monohydrates, dihydrates and the like.
A prodrug, as an equivalent compound of a novel phenol derivative
represented by the general formula (1) of the present invention, or
a pharmaceutically acceptable salt thereof, or a hydrate thereof or
a solvate thereof, also falls within the scope of the present
invention. The "prodrug" means a compound which is converted into a
compound (1) by in vivo metabolism mechanism, that is, a compound
which enzymatically causes oxidation, reduction or hydrolysis in
vivo, or causes hydrolysis by gastric acid thereby converting into
a compound of the general formula (1). Examples of the prodrug of
the general formula (1) include compounds in which a phenolic
hydroxyl group is modified with an acyl group, an alkyl group and
the like, for example, acetylated and pivaloylated compounds.
These compounds can be synthesized from the compound (1) by a known
method. The prodrug of the compound (1) may be a prodrug which is
converted into the compound (1) under the conditions described in
"Soyaku Kagaku", pp. 204-208, published in 2004 by Tokyo Kagaku
Dojin Co. Ltd.
There is no particular limitation on the method for the synthesis
of the compounds of the present invention and, for example, they
can be synthesized in accordance with the following steps. In that
case, they can be sometimes produced, effectively from the
viewpoint of a synthetic technique, by introducing an appropriate
protective group into a functional group in a starting material or
an intermediate, depending on the type of the functional group.
Examples of such a functional group include an amino group, a
hydroxy group, a carboxy group and the like. When the synthesis is
performed by introducing a protective group into the functional
group, a desired compound can be obtained by appropriately removing
the protective group in the respective synthesis stages. Examples
of the type of such a protective group and methods for protection
and deprotection thereof include those described in, for example,
Greene and Wuts, "Protective Groups in Organic Synthesis (Fourth
Edition)", and the like.
Advantageous Effects of the Invention
A novel phenol derivative of the present invention, or a
pharmaceutically acceptable salt thereof or a hydrate thereof or a
solvate thereof exhibits high concentration of an unchanged
compound in urine, and also has excellent uricosuric action and are
excellent in safety, and is therefore useful as a pharmaceutical
for the acceleration of excretion of uric acid; a pharmaceutical
for the reduction of the amount of uric acid and/or concentration
of uric acid in blood and/or in tissue; a pharmaceutical for use in
the prevention and/or treatment of a disease associated with uric
acid in blood and/or in tissue; a pharmaceutical for use in the
prevention and/or treatment of hyperuricaemia; and a pharmaceutical
for use in the prevention and/or treatment of a disease associated
with hyperuricaemia and/or a disease accompanied by
hyperuricaemia.
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 is a general formula showing a novel phenol derivative of
the present invention.
DESCRIPTION OF EMBODIMENTS
A typical method for the synthesis of novel phenol derivatives
represented by the following general formula (1) of the present
invention will be described below.
<Production Method>
##STR00002##
First step: Acid chloride (3) can be synthesized from a carboxylic
acid intermediate (2) as a starting material in an organic solvent,
using thionyl chloride, phosphorous pentachloride, phosphorous
trichloride, phosphorous oxychloride, oxalyl chloride and the
like.
Second step: 2,3-dihydro-1,3-benzothiazole (5) substituted with R3
can be obtained by reacting a 2-aminobenzenethiol (4) substituted
with R3 with an aqueous formalin solution, or a formaldehyde
equivalent such as paraformaldehyde.
Third step: An amide compound (6) can be synthesized by condensing
acid chloride whose phenol is protected, synthesized in the first
step, and 2,3-dihydro-1,3-benzothiazole substituted with R3
synthesized in the second step in the presence of a conventional
base.
Fourth step: When R1, R2 and R3 of the amide compound (6) are
functional groups which are not influenced by oxidation, sulfoxide
or sulfone can be obtained by conventional oxidation using an
organic acid peroxide such as perchlorobenzoic acid or peracetic
acid, hydrogen peroxide and a catalyst. When R1 is a functional
group which is influenced by oxidation, for example, an
alkylsulfanyl group or the like, a sulfone derivative can be
synthesized by simultaneously performing oxidation. In case of
synthesizing a derivative in which R1 is an alkylsulfanyl group,
the derivative can be obtained from a compound in which R1 is a
halogen group such as iodine, using a coupling reaction or the
like.
Fifth step: With respect to deprotection of a protected
phenolhydroxyl group, for example, the objective product (1) can be
synthesized under the deprotection condition described in
"Protective Groups in Organic Synthesis (Fourth Edition)" (written
by Greene and Wuts). For example, when a protective group is a
methyl group, the objective product (1) can be obtained by heating
at least equivalent amount of lithium chloride in
N,N-dimethylformamide. In case of a benzyl group, the objective
product (1) can be obtained by performing catalytic hydrogenation
in the presence of a catalyst such as palladium.
The carboxylic acid intermediate (2) to be used in the first step
can be synthesized from the respective starting materials by
performing the following conventional reaction operation, as shown
in the following scheme.
##STR00003##
Synthesis method i) Method for the synthesis of a 4-hydroxybenzoic
acid ester substituted at the 3-position: For example, with respect
to a compound in which R5 is a trifluoromethoxy group, it is
possible to synthesize a compound (11) in which R5 is a
trifluoromethoxy group, which is a starting material of the
synthesis method ii), by acetylating 2-trifluoromethoxyphenol (8)
with acetic anhydride or the like, performing Fries rearrangement
using trifluoromethanesulfonic acid or the like, and then
performing protection of hydroxyl group and esterification by a
haloform reaction.
Synthesis method ii) It is possible to synthesize a compound in
which R6 is a halogen atom and R5 is a cyano group, a
trifluoromethyl group or a trifluoromethoxy group from the
4-hydroxybenzoic acid ester (11) substituted at the 3-position by
the following procedure.
##STR00004## For example, it is possible to synthesize an ester
intermediate (13) in which R6 is a halogen atom and R5 is a cyano
group by halogenating the 3-cyano-4-hydroxybenzoic acid ester (11)
with a conventional halogenating agent such as N-chlorosuccinimide
(NCS), N-bromosuccinimide (NBS) or N-iodosuccinimide (NIS), and
then reacting a phenolhydroxyl group with dimethylsulfuric acid,
benzylbromide or the like in the presence of a conventional base
thereby protecting with R4 (methyl group, benzyl group, etc.). Thus
obtained ester intermediate (13) is subjected to a conventional
hydrolysis reaction to obtain a carboxylic acid intermediate (14).
Under the following hydrolysis condition, for example, the
carboxylic acid intermediate can be synthesized by reacting at room
temperature or under thermal refluxing in an organic solvent,
water, or a mixed solvent with an organic solvent in the presence
of the reaction corresponding amount of an acid or a base. Examples
of the acid include hydrochloric acid, sulfuric acid, hydrobromic
acid, trifluoroacetic acid and the like, and examples of the base
include sodium hydroxide, lithium hydroxide and the like.
With respect to an ester intermediate (13-1) in which R6 is an
iodine atom, the iodine atom can be converted into a functional
group which can be introduced by a general coupling reaction.
##STR00005##
For example, it is possible to synthesize an ester intermediate
(15-1) in which R7 is an alkyl group, an alkynyl group or an
alkylsulfanyl group from an ester intermediate (13-1-1) in which R5
is a cyano group and R6 is an iodine atom in the presence of a
catalyst such as palladium or nickel, using an organoboron
compound, alkyne, dialkyl disulfide and the like. It is also
possible to convert a derivative of alkyne obtained herein into an
alkene derivative, an alkyl derivative and the like by performing a
conventional catalytic reduction using a palladium catalyst,
hydrogen gas and the like. It is also possible to synthesize an
ester intermediate (15-2) in which R5 is a cyano group and R7 is a
trifluoromethyl group by reacting the ester intermediate (13-1-1)
with methyl fluorosulfonyl difluoroacetate under heating in the
presence of copper iodide. It is also possible to perform these
coupling reactions in a state (12-1) where a protective group of R4
is absent. An ester intermediate (15) whose phenolhydroxyl group is
protected is subjected to a conventional hydrolysis reaction to
obtain a carboxylic acid intermediate (16).
Synthesis method iii) When R8 is a functional group which does not
exert an influence on the subsequent reaction, for example, an
alkyl group, a trifluoromethyl group, an alkoxy group or the like,
a carboxylic acid intermediate (23) can be synthesized using, as a
starting material, a phenol (17) substituted with R8 at the
2-position.
##STR00006##
A hydroxyl group of the phenol substituted with R8 at the
2-position is protected with a methoxymethyl group or the like,
lithiated with an organoithium reagent (n-butyllithium,
s-butyllithium, methyllithium, etc.) and formylated with
N,N-dimethylformamide (DMF), and then protective group of the
hydroxyl group is deprotected to obtain a salicylaldehyde (19)
substituted at the 3-position. It is possible to obtain (21) by
performing bromination of a hydroxyl group at the para-position,
protection of a hydroxyl group and protection of a formyl group. It
is possible to synthesize 3-formyl-4-alkoxybenzoic acid (22)
substituted with R8 at the 5-position by adding a magnesium and an
activating agent to prepare a Grignard reagent, reacting with
carbon dioxide and then deprotecting under acidic conditions. It is
possible to synthesize a carboxylic acid intermediate (23)
substituted with a cyano group at the 3-position by reacting
3-formyl-4-alkoxybenzoic acid (22) with hydroxylamine to obtain
oxime, and then subjecting the oxime to a dehydration reaction
thereby converting a formyl group into a cyano group.
It is also possible to synthesize a carboxylic acid intermediate
(26) substituted with a carbamoyl group at the 3-position by
esterifying carboxylic acid (22) and oxidizing a formyl group to
obtain carboxylic acid (24), reacting the carboxylic acid with
amine in the presence of a condensing agent, and then performing an
ester hydrolysis.
##STR00007##
The compounds of the general formula (1) synthesized as described
above can be isolated and purified in a free form or in the form of
a salt by conventional chemical operations such as extraction,
concentration, distillation, crystallization, filtration,
recrystallization, various chromatographies and the like.
Furthermore, optical isomers, stereoisomers and position isomers of
the compounds can be respectively isolated by a fractionation
recrystallization method, a chiral column method, a diastereomer
method or the like.
A pharmaceutical composition comprising, as active ingredient(s),
substance(s) selected from the group consisting of a compound
represented by the general formula (1) and a pharmaceutically
acceptable salt thereof, and a hydrate thereof and a solvate
thereof may be used as it is, or may be used as a formulation
comprising one, or two or more kinds of pharmaceutical additive(s).
The pharmaceutical composition may be used in any dosage form and
can be used as tablets, pills, capsules, powders, subtilized
granules, granules, solutions, suspensions, syrups, injections,
external preparations, suppositories and the like.
There is no particular limitation on types of pharmaceutical
additives when a pharmaceutical composition comprising, as active
ingredients, substance(s) selected from the group consisting of a
compound represented by the general formula (1) and a
pharmaceutically acceptable salt thereof, and a hydrate thereof and
a solvate thereof is used as the above pharmaceutical formulation,
and it is possible to use bases, excipients, lubricants, coating
agents, sugar coating agents, wetting agents, binders,
disintegrating agents, solvents, solubilizers, dissolving agents,
dissolving aids, suspending agents, dispersing agents, emulsifiers,
surfactants, isotonic agents, buffering agents, pH modifiers,
soothing agents, antiseptics, preservatives, stabilizers,
antioxidants, colorants, sweeteners and the like alone, or in
appropriate combination.
Examples of the bases include kaolin, cacao butter, corn starch,
dried aluminum hydroxide gel, crystalline cellulose, methyl
cellulose, hydroxypropyl cellulose, macrogol and the like. Examples
of the excipients include lactose, sucrose, starch, D-mannitol,
corn starch, crystalline cellulose, cellulose derivatives
(hydroxypropyl cellulose, carmellose calcium, low substituted
hydroxypropyl cellulose, etc.), light anhydrous silicic acid,
calcium hydrogen phosphate and the like. Examples of the lubricants
include magnesium stearate, calcium stearate, talc, titanium oxide
and the like. Examples of the coating agents include carmellose
calcium, titanium oxide, aluminum stearate, talc and the like.
Examples of the sugar coating agents include sucrose, lactose,
gelatin, paraffin, crystalline cellulose and the like. Examples of
the wetting agents include glycerol, urine, macrogol and the like.
Examples of the binders include crystalline cellulose, sucrose,
powdered gum arabic, sodium arginate, carboxymethylethyl cellulose,
starch, sucrose, purified gelatin, dextrin, methyl cellulose,
carboxymethyl cellulose, sodium carboxymethyl cellulose,
carboxymethylethyl cellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose, hydroxypropylmethyl cellulose, pullulan, polyvinyl
alcohol, polyvinyl pyrrolidone and the like. Examples of the
disintegrating agent include sucrose, lactose, starch, agar powder,
crospovidone, carboxymethyl cellulose, sodium carboxymethyl starch,
carmellose, hydroxypropylmethyl cellulose, citric anhydride, sodium
lauryl sulfate, calcium dihydrogen phosphate and the like. Examples
of the solvents include purified water, water for injection,
ethanol, glycerol, propylene glycol, macrogol, sesame oil, corn
oil, hydrochloric acid, acetic acid and the like. Examples of the
solubilizers include glycerol, polyoxyl stearate, polysorbate,
macrogol and the like. Examples of the dissolving agents include,
in addition to those used as the solvents mentioned above, sodium
hydroxide, sodium carbonate, meglumine and the like. Examples of
the dissolving aids include hydrochloric acid, acetic acid, citric
acid, sodium citrate, aspartic acid, sodium hydroxide, ethanol,
propylene glycol, D-mannitol, sodium benzoate, benzyl benzoate,
urine, triethanolamine, polysorbate, polyvinylpyrrolidone, macrogol
and the like. Examples of the suspending agents include gum arabic,
benzalkonium chloride, kaolin, carmellose, sodium lauryl sulfate,
laurylaminopropionic acid, glyceryl monostearate, polyvinyl
alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose sodium,
methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose,
hydroxypropyl cellulose and the like. Examples of the dispersing
agents include sodium citrate, light aluminum oxide, titanium
oxide, zinc stearate, polysorbate, macrogol, dextrin, low
substituted hydroxypropyl cellulose, hydroxypropyl cellulose and
the like. Examples of the emulsifiers include benzalkonium
chloride, glycerol, propylene glycol, cetanol, lecithin, lanolin,
sodium lauryl sulfate and the like. Examples of the surfactant
include squalane, cetanol, polyoxyethylene cetyl ether,
lauromacrogol and the like. Examples of the isotonic agents include
glucose, D-sorbitol, sodium chloride, glycerol, D-mannitol and the
like. Examples of the buffering agents include buffer solutions
such as phosphate, acetate, carbonate, citrate buffers and the
like. Examples of the pH modifiers include inorganic acids such as
hydrochloric acid and phosphoric acid, and salts thereof, organic
acids such as acetic acid, citric acid, and lactic acid, and salts
thereof and the like. Examples of the soothing agents include
creatinine, benzyl alcohol and the like. Examples of the
antiseptics include p-oxybenzoic acid esters, chlorobutanol, benzyl
alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the
like. Examples of the preservatives include benzoic acid,
p-oxybenzoic acid esters, sorbic acid, and the like. Examples of
the stabilizers include taurine, amino acid, p-oxybenzoic acid
esters, benzyl alcohol, crystalline cellulose, macrogol and the
like. Examples of the antioxidants include sulfite, ascorbic acid
and the like. Examples of the colorants include edible dyes,
.beta.-carotene, riboflavin and the like. Examples of the
sweeteners include aspartame, sucrose, D-sorbitol, maltose and the
like. Examples of aromatics include bitter essence, bitter base and
the like.
A novel phenol derivative of the present invention exhibits high
concentration of an unchanged compound in urine and has a
remarkable uricosuric action, and therefore the novel phenol
derivative or a pharmaceutically acceptable salt thereof, or a
hydrate thereof or a solvate thereof is useful as a pharmaceutical
for the control of reabsorption of uric acid and the acceleration
of excretion of uric acid; a pharmaceutical for the reduction of
the amount of uric acid and/or concentration of uric acid in blood
and/or in tissue; a pharmaceutical for use in the prevention and/or
treatment of a disease associated with uric acid in blood and/or in
tissue; a pharmaceutical for use in the prevention and/or treatment
of hyperuricaemia; and a pharmaceutical for use in the prevention
and/or treatment of a disease associated with hyperuricaemia and/or
a disease accompanied by hyperuricaemia.
There is no particular limitation on the "disease associated with
uric acid in blood and/or in tissue" or the "disease associated
with hyperuricaemia and/or a disease accompanied by hyperuricaemia"
as long as the disease is a disease associated with uric acid
regardless of direct or indirect association or a disease suspected
to be associated with uric acid and/or a disease complicated by
these diseases. Examples thereof include gout, urinary stone,
obesity, hyperlipemia, abnormal glucose tolerance, diabetes,
metabolic syndrome, renal disease, cerebral haemorrhage and/or
cardiovascular disease, and complications of these diseases can
also be included.
There is no particular limitation on the subject of gout as long as
it has a disease state which meets or conforms to the diagnosis
criteria. For example, those having at least one disease state of
gouty node, gouty arthritis and gouty kidney are included. Examples
of the renal disease include, but are not particularly limited to,
renal insufficiency, albuminuria, nephritis, uremia, ESRD and the
like. Examples of the cerebrovascular disease include, but are not
particularly limited to, cerebrovascular accident, dementia and the
like. Examples of the cardiovascular disease include, but are not
particularly limited to, hypertension, coronary artery disease,
carotid artery disease, arteriosclerosis, cardiac hypertrophy,
thrombosis, endothelial dysfunction and/or cardiovascular diseases
(stenocardia, myocardial infarction, etc.).
Furthermore, a novel phenol derivative of the present invention can
be used in combination with other remedies and/or preventives of
the above-mentioned diseases, and is useful for effectively dealing
with the diseases. The novel phenol derivative of the present
invention is useful in that it can suppress an increase in blood
urate level by using in combination with a drug which brings about
an increase in blood urate level (for example, antihypertensive
diuretic, antituberculosis drug, lipid-lowering drug,
antiinflammatory analgesic, asthmaremedy, immunosuppressive drug,
antimetabolite, anticancer drug, etc.). It is suggested that the
substance capable of decreasing a blood urate level (allopurinol)
is effective for neurodegenerative diseases (Alzheimer's disease,
Parkinson's disease, Huntington's disease, amyotrophic lateral
sclerosis, etc.), pancreatitis and sleep apnea syndrome. Therefore,
it is also possible to apply a novel phenol derivative of the
present invention or a pharmaceutically acceptable salt thereof, or
a hydrate thereof or a solvate thereof for the prevention and/or
treatment of neurodegenerative diseases, digestive system diseases
such as pancreatitis, and respiratory tract diseases such as sleep
apnea syndrome.
Dose and the number of dose of the compounds of the present
invention or a pharmaceutical composition containing the compounds
can be appropriately selected depending on patient's symptoms, age
and sex, dosage form and the type of a drug used in combination and
the like. For example, a daily dose for adults can be usually
selected from the range of 0.1 to 1,000 mg, preferably 1 to 500 mg,
and the aforementioned dose can be administered once a day or
several times as divided portions. The pharmaceutical composition
of the present invention may be administered alone, or may be
administered in combination with other pharmaceuticals having the
same and/or different effectiveness.
EXAMPLES
The present invention will be specifically described below by way
of Examples, but the present invention is not limited to the
following Examples.
The meanings of the abbreviations used in the Examples are as
follows:
1H-NMR: proton nuclear magnetic resonance spectrum, CDCl3:
deuterium chloroform, DMSO-d6: deuterium dimethyl sulfoxide, CD3OD:
deuterium methanol, Hz: hertz, J: coupling constant, m: multiplet,
sevent: seventet, quint: quintet, q: quartet, dt: double triplet,
dd: double doublet, ddd: double double doublet, t: triplet, d:
doublet, s: singlet, brs: broad singlet, M: molar concentration and
N: noral. NMR means 270 MHz nuclear magnetic resonance spectrum and
tetramethylsilane (TMS) was used as an internal standard substance.
MS means mass spectrometry, and an instrument using an electrospray
ionization (ESI) method as an ionization method was used.
Example 1
3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole
(a) Synthesis of 2,3-dihydro-1,3-benzothiazole
37% formalin (5.2 mL) was diluted with water (80 mL), and
diisopropylether (80 mL) and 2-aminobenzenethiol (7.84 g) were
added, and then the mixture was stirred at mom temperature for 30
minutes. The organic layer was separated and the aqueous layer was
extracted with diisopropylether. The organic layers were combined,
washed with saturated brine and then dried over anhydrous sodium
sulfate. The solvent was distilled off under reduced pressure and
the obtained residue was used for the synthesis of (c).
(b) Synthesis of 3,5-dichloro-4-methoxybenzoyl chloride
To 3,5-dichloro-4-methoxybenzoic acid (8.81 g), toluene (170 mL),
N,N-dimethylformamide (5 droplets) and thionyl chloride (6.0 mL)
were added, and then the mixture was stirred at 60.degree. C. for
16 hours. The solvent was distilled off under reduced pressure and
the obtained residue was azeotroped with toluene and then used for
the synthesis of (c).
(c) Synthesis of
3-(3,5-dichloro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole
2,3-dihydro-1,3-benzothiazole was dissolved in chloroform (50 mL),
and triethylamine (17.4 mL) and 3,5-dichloro-4-methoxybenzoyl
chloride were added to the solution, and then the mixture was
stirred at room temperature for 1 hour. The solvent was distilled
off under reduced pressure and water was added, and then the
mixture was extracted with ethyl acetate. The organic layer was
washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated
brine, and then dried over anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure and the obtained residue
was used for the synthesis of (d).
(d) Synthesis of
3-(3,5-dichloro-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole
3-(3,5-dichloro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole was
dissolved in chloroform (230 mL), and 70% metachloroperbenzoic acid
(43.25 g) was added to the solution at 0.degree. C., and then the
mixture was stirred at room temperature for 20 hours and quenched
with 10% sodium thiosulfate. The solvent was distilled off under
reduced pressure and 1N sodium hydroxide was added, and then the
mixture was extracted with ethyl acetate. The organic layer was
washed with 1N sodium hydroxide and saturated brine, and then dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure to obtain the title compound (13.25 g) as a
colorless crystal.
(e) Synthesis of
3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole
3-(3,5-dichloro-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole
(1.00 g) was dissolved in N,N-dimethylformamide (5 mL), and lithium
chloride (570 mg) was added, and then the mixture was stirred at
130.degree. C. for 2 hours. To the reaction solution, 1N
hydrochloric acid was added, and then the reaction mixture was
extracted with ethyl acetate. The organic layer was washed with 1N
hydrochloric acid and saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure and the obtained residue was crystallized from
ethanol to obtain the title compound (749 mg) as a colorless
crystal.
1H-NMR.delta. (DMSO-d6): 5.35 (2H, s), 7.44 (1H, dd, J=7.6, 7.6
Hz), 7.74 (2H, s), 7.76 (1H, dd, J=8.4, 7.6 Hz), 7.90 (1H, d, J=7.6
Hz), 8.04 (1H, d, J=8.4 Hz), 11.04 (1H, brs). MS (m/z): 356 (M-H)-,
358 (M+2-H)-.
Example 2
3-(3,5-dichloro-4-hydroxybenzoyl)-2,3-dihydro-1,3-benzothiazole
3-(3,5-dichloro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole
(300 mg) was dissolved in N,N-dimethylformamide (6 mL), and lithium
chloride (374 mg) was added to the solution, and then the mixture
was stirred at 120.degree. C. for 16 hours. To the reaction
solution, 1N hydrochloric acid was added, and then the reaction
mixture was extracted with ethyl acetate. The organic layer was
washed with 1N hydrochloric acid and saturated brine, and then
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure and the obtained residue was crystallized
from n-hexane-ethyl acetate to obtain the title compound (214 mg)
as a brown crystal.
1H-NMR.delta. (DMSO-d6): 5.36 (2H, s), 7.03-7.13 (2H, m), 7.31-7.37
(1H, m), 7.50 (1H, brs), 7.65 (2H, s), 10.89 (1H, brs). MS (m/z):
324 (M-H)-, 326 (M+2-H)-.
Example 3
3-(3,5-dichloro-4-hydroxybenzoyl)-1-oxo-2,3-dihydro-1,3-benzothiazole
(a) Synthesis of
3-(3,5-dichloro-4-methoxybenzoyl)-1-oxo-2,3-dihydro-1,3-benzothiazole
3-(3,5-dichloro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole
(500 mg) was dissolved in chloroform (10 mL), and 70%
metachloroperbenzoic acid (320 mg) was added to the solution, and
the mixture was stirred at 0.degree. C. for 10 minutes. The solvent
was distilled off under reduced pressure and water was added, and
then the mixture was extracted with ethyl acetate. The organic
layer was washed with 1N sodium hydroxide and saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure and the obtained residue was purified by
silica gel column chromatography (n-hexane:ethyl acetate=1:1) to
obtain the title compound (336 mg) as a colorless crystal.
(b) Synthesis of
3-(3,5-dichloro-4-hydroxybenzoyl)-1-oxo-2,3-dihydro-1,3-benzothiazole
3-(3,5-dichloro-4-methoxybenzoyl)-1-oxo-2,3-dihydro-1,3-benzothiazole
(336 mg) was dissolved in N,N-dimethylformamide (6 mL) and lithium
chloride (400 mg) was added to the solution, and then the mixture
was stirred at 120.degree. C. for 16 hours. To the reaction
solution, 1N hydrochloric acid was added, and then the reaction
mixture was extracted with ethyl acetate. The organic layer was
washed with 1N hydrochloric acid and saturated brine, and then
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure and the obtained residue was crystallized
from ethyl acetate-methanol to obtain the title compound (220 mg)
as a brown crystal.
1H-NMR.delta. (DMSO-d6): 5.07 (2H, s), 7.38 (1H, dd, J=7.6, 7.6
Hz), 7.70 (1H, ddd, J=8.3, 7.6, 0.8 Hz), 7.73 (2H, s), 8.00 (1H, d,
J=8.3 Hz), 8.07 (1H, d, J=7.6 Hz), 11.06 (1H, brs). MS (m/z): 340
(M-H)-, 342 (M+2-H)-.
Example 4
3-(3-cyano-4-hydroxy-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-b-
enzothiazole
(a) Synthesis of 1-methoxymethoxy-2-trifluoromethylbenzene
2-trifluoromethylphenol (50.00 g) was dissolved in
N,N-dimethylformamide (100 mL), and potassium carbonate (85.14 g)
and chloromethyl methyl ether (34.7 mL) were added to the solution,
and then the mixture was stirred under water cooling for 1 hour.
Water was added to the reaction solution, and then the mixture was
extracted with n-hexane. The organic layer was washed with water
and saturated brine, and then dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure to obtain the
title compound (64.13 g) as a colorless oily substance.
(b) Synthesis of 2-hydroxy-3-trifluoromethylbenzaldehyde
1-methoxymethoxy-2-trifluoromethylbenzene (64.13 g) was dissolved
in tetrahydrofuran (500 mL), and a 2.77M n-butyllithium-n-hexane
solution (123 mL) was added to the solution over 45 minutes under
an argon gas flow at -70.degree. C., and then the mixture was
stirred for 1 hour. N,N-dimethylformamide (28.5 mL) was added,
followed by stirring at room temperature for 30 minutes. 4N
hydrochloric acid (310 mL) was added, followed by stirring at
60.degree. C. for 19 hours. The organic solvent was distilled off
under reduced pressure, and the mixture was extracted with ethyl
acetate. The organic layer was washed with saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure to obtain the title compound (59.16 g)
as a yellow crystal.
(c) Synthesis of
5-bromo-2-hydroxy-3-trifluoromethylbenzaldehyde
2-hydroxy-3-trifluoromethylbenzaldehyde (59.16 g) was dissolved in
acetonitrile (500 mL), and N-bromosuccinimide (57.56 g) was added
to the solution, and then the mixture was stirred at 0.degree. C.
for 1 hour. The solvent was distilled off under reduced pressure
and water was added, and then the mixture was extracted with ethyl
acetate. The organic layer was washed with saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure and the obtained crystal was washed with
n-hexane (50 mL) to obtain the title compound (63.98 g) as a pale
yellow crystal.
(d) Synthesis of
5-bromo-2-methoxy-3-trifluoromethylbenzaldehyde
5-bromo-2-hydroxy-3-trifluoromethylbenzaldehyde (63.98 g) was
dissolved in N,N-dimethylformamide (130 mL), and potassium
carbonate (65.79 g) and dimethylsulfuric acid (31.6 mL) were added
to the solution under water cooling, and then the mixture was
stirred at room temperature for 3 hours. Water was added to the
reaction solution, and then the mixture was extracted with ethyl
acetate. The organic layer was washed with 1N hydrochloric acid and
saturated brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure to obtain the
title compound (66.19 g) as a brown crystal.
(e) Synthesis of
5-bromo-1-diethoxymethyl-2-methoxy-3-trifluoromethylbenzene
5-bromo-2-methoxy-3-trifluoromethylbenzaldehyde (66.19 g) was
dissolved in n-hexane (130 mL) and triethyl orthoformate (51 mL),
and Amberlyst-15 (6.62 g) was added to the solution, and then the
mixture was refluxed for 3 hours. The reaction solution was
filtered, and then the solvent was distilled off under reduced
pressure to obtain the title compound (82.81 g) as a brown oily
substance.
(f) Synthesis of 3-formyl-4-methoxy-5-trifluoromethylbenzoic
acid
To magnesium (5.97 g), tetrahydrofuran (230 mL) and
5-bromo-1-diethoxymethyl-2-methoxy-3-trifluoromethylbenzene (31.55
g) were added, and then the mixture was stirred at room temperature
for 90 minutes. The reaction solution was cooled to 0.degree. C.
and stirred for 1 hour under a carbon dioxide atmosphere, and then
2N hydrochloric acid (240 mL) was added and the mixture was stirred
at room temperature for 16 hours. The organic solvent was distilled
off under reduced pressure, and then the mixture was extracted with
diisopropylether. The organic layer was extracted with 1N sodium
hydroxide (100 mL) added thereto, and then the aqueous layer was
washed twice with diisopropylether. The reaction mixture was
acidified with 4N hydrochloric acid added thereto, and then
extracted with ethyl acetate. The organic layer was washed with
saturated brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure to obtain the
title compound (50.05 g) as a brown solid.
(g) Synthesis of 3-cyano-4-methoxy-5-trifluoromethylbenzoic
acid
3-formyl-4-methoxy-5-trifluoromethylbenzoic acid (58.04 g) was
dissolved in formic acid (290 mL), and hydroxylamine hydrochloride
(17.07 g) was added to the solution, and the mixture was refluxed
for 19 hours. The solvent was distilled off under reduced pressure
and water was added, and then the mixture was extracted with ethyl
acetate. The organic layer was washed with saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure to obtain the title compound (15.62 g)
as a brown solid.
1H-NMR.delta. (DMSO-d6): 4.23 (3H, s), 8.33 (1H, d, J=2.1 Hz), 8.55
(1H, d, J=2.1 Hz). MS (m/z): 244 (M-H)-.
(h) Synthesis of
3-cyano-4-methoxy-5-trifluoromethylbenzoylchloride
To 3-cyano-4-methoxy-5-trifluoromethylbenzoic acid (8.10 g),
toluene (160 mL), N,N-dimethylformamide (5 droplets) and thionyl
chloride (4.80 mL) were added, and the mixture was stirred at
60.degree. C. for 16 hours. The solvent was distilled off under
reduced pressure and the obtained residue was azeotroped with
toluene and then used for the synthesis of (i).
(i) Synthesis of
3-(3-cyano-4-methoxy-5-trifluoromethylbenzoyl)-2,3-dihydro-1,3-benzothiaz-
ole
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol
(5.00 g) and 37% formalin (3.0 mL) in the same manner as in the
synthesis of Example 1 was dissolved in chloroform (50 mL), and
triethylamine (11.1 mL) and
3-cyano-4-methoxy-5-trifluoromethylbenzoylchloride were added to
the solution, and then the mixture was stirred at room temperature
for 1 hour. The solvent was distilled off under reduced pressure
and water was added, and then the mixture was extracted with ethyl
acetate. The organic layer was washed with 1N hydrochloric acid, 1N
sodium hydroxide and saturated brine, and then dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure and the obtained residue was used for the synthesis of
(j).
(j) Synthesis of
3-(3-cyano-4-methoxy-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3--
benzothiazole
3-(3-cyano-4-methoxy-5-trifluoromethylbenzoyl)-2,3-dihydro-1,3-benzothiaz-
ole was dissolved in chloroform (200 mL), and 70%
metachloroperbenzoic acid (21.40 g) was added to the solution, and
then the mixture was stirred at room temperature for 20 hours and
quenched with 10% sodium thiosulfate. The solvent was distilled off
under reduced pressure and 1N sodium hydroxide was added, and then
the mixture was extracted with ethyl acetate. The organic layer was
washed with 1N sodium hydroxide and saturated brine, and then dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure to obtain the title compound (4.08 g) as a pale
yellow solid.
(k) Synthesis of
3-(3-cyano-4-hydroxy-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3--
benzothiazole
3-(3-cyano-4-methoxy-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3--
benzothiazole (4.08 g) was dissolved in N,N-dimethylformamide (40
mL), and lithium chloride (1.74 g) was added to the solution, and
then the mixture was stirred at 70.degree. C. for 2 hours. To the
reaction solution, 1N hydrochloric acid was added, and then the
reaction mixture was extracted with ethyl acetate. The organic
layer was washed with 1N hydrochloric acid and saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure and the obtained residue was
crystallized from n-hexane-ethyl acetate to obtain the title
compound (222 g) as a colorless crystal.
1H-NMR.delta. (DMSO-d6): 5.37 (2H, s), 7.44 (1H, dd, J=7.8, 7.8
Hz), 7.77 (1H, ddd, J=7.9, 7.8, 1.3 Hz), 7.91 (1H, dd, J=7.8, 1.3
Hz), 8.09 (1H, d, J=7.9 Hz), 8.10 (1H, d, J=2.1 Hz), 8.27 (1H, d,
J=2.1 Hz). MS (m/z): 381 (M-H)-.
Example 5
3-(3-cyano-4-hydroxy-5-trifluoromethylbenzoyl)-2,3-dihydro-1,3-benzothiazo-
le
3-(3-cyano-4-methoxy-5-trifluoromethylbenzoyl)-2,3-dihydro-1,3-benzothiaz-
ole (232 mg) was dissolved in N,N-dimethylformamide (3 mL), and
lithium chloride (108 mg) was added to the solution, and then the
mixture was stirred at 70.degree. C. for 1 hour. To the reaction
solution, 1N hydrochloric acid was added, and then the mixture was
extracted with ethyl acetate. The organic layer was washed with 1N
hydrochloric acid and saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure and the obtained residue was crystallized from
n-hexane-ethyl acetate to obtain the title compound (131 mg) as a
brown crystal.
1H-NMR.delta. (DMSO-d6): 5.38 (2H, s), 7.04-7.14 (2H, m), 7.32-7.38
(1H, m), 7.55 (1H, br), 8.05 (1H, d, J=2.1 Hz), 8.22 (1H, d, J=2.1
Hz). MS (m/z): 349 (M-H)-.
Example 6
3-(3-cyano-4-hydroxy-5-trifluoromethylbenzoyl)-1-oxo-2,3-dihydro-1,3-benzo-
thiazole
(a) Synthesis of
3-(3-cyano-4-methoxy-5-trifluoromethylbenzoyl)-1-oxo-2,3-dihydro-1,3-benz-
othiazole
3-(3-cyano-4-methoxy-5-trifluoromethylbenzoyl)-2,3-dihydro-1,3-benzothiaz-
ole (594 mg) was dissolved in chloroform (10 mL), and 70%
metachloroperbenzoic acid (433 mg) was added to the solution, and
then the mixture was stirred at 0.degree. C. for 5 minutes. The
organic solvent was distilled off under reduced pressure, and then
1N sodium hydroxide was added and the precipitated crystal was
washed with 1N sodium hydroxide and water to obtain the title
compound (619 mg) as a colorless crystal.
(b) Synthesis of
3-(3-cyano-4-hydroxy-5-trifluoromethylbenzoyl)-1-oxo-2,3-dihydro-1,3-benz-
othiazole
3-(3-cyano-4-methoxy-5-trifluoromethylbenzoyl)-1-oxo-2,3-dihydro-1,3-benz-
othiazole (619 mg) was dissolved in N,N-dimethylformamide (5 mL),
and lithium chloride (276 mg) was added to the solution, and the
mixture was stirred at 70.degree. C. for 3 hours. To the reaction
solution, 1N hydrochloric acid was added, and then the reaction
mixture was extracted with ethyl acetate. The organic layer was
washed with 1N hydrochloric acid and saturated brine, and then
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure to obtain the title compound (494 mg) as a
colorless crystal.
1H-NMR.delta. (DMSO-d6): 5.09 (1H, d, J=13.0 Hz), 5.15 (1H, d,
J=13.0 Hz), 7.40 (1H, dd, J=7.5, 7.5 Hz), 7.72 (1H, ddd, J=7.5,
7.5, 1.0 Hz), 8.06 (1H, d, J=7.5 Hz), 8.09 (1H, d, J=7.5 Hz), 8.12
(1H, d, J=1.8 Hz), 8.30 (1H, d, J=1.8 Hz). MS (m/z): 365
(M-H)-.
Example 7
3-(3-chloro-5-cyano-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiaz-
ole
(a) Synthesis of methyl 3-chloro-5-cyano-4-hydroxybenzoate
Methyl 3-cyano-4-hydroxybenzoate (2.00 g) was dissolved in
chloroform (15 mL) and methanol (5 mL), and N-chlorosuccinimide
(3.62 g) and 4N hydrochloric acid-ethyl acetate (6.8 mL) were added
to the solution, and then the mixture was stirred at room
temperature for 1 hour. The solvent was distilled off under reduced
pressure and a mixture of methanol and water in a mixing ratio of
9:1 was added, and then the precipitated crystal was washed with
water and isopropyl alcohol to obtain the title compound (1.27 g)
as a colorless crystal.
(b) Synthesis of methyl 3-chloro-5-cyano-4-methoxybenzoate
Methyl 3-chloro-5-cyano-4-hydroxybenzoate (1.27 g) was dissolved in
N,N-dimethylformamide (20 mL), and potassium carbonate (5.00 g) and
dimethylsulfuric acid (1.70 mL) were added to the solution, and
then the mixture was stirred at room temperature for 18 hours. The
reaction solution was filtered and water was added, and then the
reaction mixture was extracted with ethyl acetate. The organic
layer was washed with water and saturated brine, and then dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure to obtain the title compound (1.03 g) as a
colorless crystal.
(c) Synthesis of 3-chloro-5-cyano-4-methoxybenzoic acid
Methyl 3-chloro-5-cyano-4-methoxybenzoate (1.02 g) was dissolved in
tetrahydrofuran (15 mL) and water (6 mL), and lithium hydroxide
monohydrate (759 mg) was added to the solution, and then the
mixture was stirred at room temperature for 90 minutes. The organic
solvent was distilled off and the aqueous layer was washed with
n-hexane. The aqueous layer was acidified with 1N hydrochloric acid
and then extracted with ethyl acetate. The organic layer was washed
with saturated brine, and then dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure to obtain the
title compound (946 mg) as a colorless crystal.
1H-NMR.delta. (DMSO-d6): 4.43 (3H, s), 8.55 (2H, s), 14.00 (1H,
brs). MS (m/z): 210 (M-H)-, 212 (M+2-H)-.
(d) Synthesis of 3-chloro-5-cyano-4-methoxybenzoyl chloride
To 3-chloro-5-cyano-4-methoxybenzoic acid (932 mg), toluene (9.3
mL), N,N-dimethylformamide (0.03 mL) and thionyl chloride (0.38 mL)
were added, and the mixture was stirred at 60.degree. C. for 16
hours. The solvent was distilled off under reduced pressure and
then azeotroped with toluene to obtain the title compound (993 mg)
as a brown solid.
(e) Synthesis of
3-(3-chloro-5-cyano-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol
(810 mg) and 37% formalin (0.53 mL) in the same manner as in the
synthesis of Example 1 was dissolved in dichloromethane (15 mL),
and triethylamine (1.90 mL) and 3-chloro-5-cyano-4-methoxybenzoyl
chloride (993 mg) were added to the solution, and then the mixture
was stirred at room temperature for 1.5 hours. The solvent was
distilled off under reduced pressure and water was added, and then
the mixture was extracted with ethyl acetate. The organic layer was
washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated
brine, and then dried over anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure and the obtained residue
was purified by silica gel column chromatography (n-hexane:ethyl
acetate=6:1) to obtain the title compound (580 mg) as a yellow oily
substance.
(f) Synthesis of
3-(3-chloro-5-cyano-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothia-
zole
3-(3-chloro-5-cyano-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole
(187 mg) was dissolved in dichloromethane (2 mL), and 70%
metachloroperbenzoic acid (607 mg) was added to the solution. After
stirring the mixture at room temperature for 5 hours, 1N sodium
hydroxide was added and then the mixture was extracted with ethyl
acetate. The organic layer was washed with 1N sodium hydroxide and
saturated brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure to obtain the
title compound (183 mg) as a pale yellow solid.
(g) Synthesis of
3-(3-chloro-5-cyano-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothia-
zole
3-(3-chloro-5-cyano-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothia-
zole (180 mg) was dissolved in N,N-dimethylformamide (2 mL), and
lithium chloride (87 mg) was added to the solution, and then the
mixture was stirred at 100.degree. C. for 1 hour. To the reaction
solution, 1N hydrochloric acid was added, and then reaction mixture
was extracted with ethyl acetate. The organic layer was washed with
1N hydrochloric acid and saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure and the obtained residue was crystallized from
n-hexane-chloroform to obtain the title compound (146 mg) as a pale
yellow crystal.
1H-NMR.delta. (DMSO-d6): 5.32 (2H, s), 7.44 (1H, ddd, J=8.4, 7.3,
0.8 Hz), 7.75 (1H, ddd, J=8.6, 7.3, 1.4 Hz), 7.88 (1H, dd, J=8.4,
1.4 Hz), 7.99 (1H, d, J=2.2 Hz), 8.00 (1H, d, J=2.2 Hz), 8.06 (1H,
d, J=8.6 Hz). MS (m/z): 347 (M-H)-.
Example 8
3-(3-chloro-5-cyano-4-hydroxybenzoyl)-2,3-dihydro-1,3-benzothiazole
3-(3-chloro-5-cyano-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole
(213 mg) was dissolved in N,N-dimethylformamide (2 mL), and lithium
chloride (111 mg) was added to the solution, and then the mixture
was stiffed at 100.degree. C. for 2 hours. To the reaction
solution, 1N hydrochloric acid was added, and then the reaction
mixture was extracted with ethyl acetate. The organic layer was
washed with 1N hydrochloric acid and saturated brine, and then
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure and the obtained residue was purified by
silica gel column chromatography (ethyl acetate:methanol=10:1), and
then crystallized from n-hexane-chloroform to obtain the title
compound (68 mg) as a pale yellow crystal.
1H-NMR.delta. (DMSO-d6): 5.37 (2H, s), 7.01-7.16 (2H, m), 7.33 (1H,
dd, J=6.5, 2.2 Hz), 7.45 (1H, d, J=7.0 Hz), 7.79 (1H, s), 7.81 (1H,
s). MS (m/z): 315 (M-H)-.
Example 9
3-(3-t-butyl-5-cyano-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothia-
zole
(a) Synthesis of methyl 3-t-butyl-4-hydroxybenzoate
Methyl 4-hydroxybenzoate (3.00 g) was dissolved in methanesulfonic
acid (15 mL), and 2-bromo-2-methylpropane (11.1 mL) was added to
the solution, and then the mixture was stirred at 70.degree. C. for
16 hours. To the reaction solution, methanol (20 mL) was added, and
then the reaction mixture was stirred at 50.degree. C. for 3 hours.
1N potassium hydroxide was added, and then the mixture was
extracted with ethyl acetate. The organic layer was washed with an
aqueous 10% potassium carbonate solution and saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure and the obtained residue was purified by
silica gel column chromatography (n-hexane:ethyl acetate=3:1) to
obtain the title compound (1.83 g) as a pale yellow crystal.
(b) Synthesis of methyl 3-t-butyl-4-hydroxy-5-iodobenzoate
Methyl 3-t-butyl-4-hydroxybenzoate (1.83 g) was dissolved in
dichloromethane (24 mL) and methanol (3 mL), and N-iodosuccinimide
(2.08 g) and trifluoromethanesulfonic acid (3 mL) were added to the
solution, and then the mixture was stirred at room temperature for
15 minutes. Water was added to the reaction solution, and then the
organic layer was separated. The organic layer was washed with 10%
sodium thiosulfate and saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure to obtain the title compound (2.77 g) as a brown
crystal.
(c) Synthesis of methyl 3-t-butyl-5-iodo-4-methoxybenzoate
Methyl 3-t-butyl-4-hydroxy-5-iodobenzoate (2.77 g) was dissolved in
N,N-dimethylformamide (50 mL), and potassium carbonate (12.0 g) and
dimethylsulfuric acid (4.1 mL) were added to the solution, and then
the mixture was stirred at room temperature for 16 hours. Water was
added to the reaction solution, and then the reaction mixture was
extracted with ethyl acetate. The organic layer was washed with
water and saturated brine, and then dried over anhydrous sodium
sulfate. The solvent was distilled off under reduced pressure to
obtain the title compound (2.77 g) as a brown crystal.
(d) Synthesis of methyl 3-t-butyl-5-cyano-4-methoxybenzoate
Methyl 3-t-butyl-5-iodo-4-methoxybenzoate (2.77 g) was dissolved in
N,N-dimethylformamide (30 mL), and copper cyanide (965 mg) was
added to the solution, and then the mixture was stirred at
150.degree. C. for 2.5 hours. To the reaction solution, 10%
potassium carbonate was added, and then the mixture was extracted
with ethyl acetate. The organic layer was washed with water and
saturated brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure and the obtained
residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=3:1) to obtain the title compound (1.48 g)
as a yellow oily substance.
(e) Synthesis of 3-t-butyl-5-cyano-4-methoxybenzoic acid
Methyl 3-t-butyl-5-cyano-4-methoxybenzoate (1.48 g) was dissolved
in methanol (20 ml), tetrahydrofuran (5 mL) and water (5 mL), and
lithium hydroxide monohydrate (753 mg) was added to the solution,
and then the mixture was stirred at room temperature for 2 hours.
To the reaction solution, 10% hydrochloric acid was added, and then
the mixture was extracted with ethyl acetate. The organic layer was
washed with saturated brine, and then dried over anhydrous sodium
sulfate. The solvent was distilled off under reduced pressure to
obtain the title compound (1.18 g) as a pale yellow crystal.
1H-NMR.delta. (CDCl3): 1.41 (9H, s), 4.26 (3H, s), 8.23 (1H, d,
J=2.2 Hz), 8.25 (1H, d, J=2.2 Hz).
(f) Synthesis of 3-t-butyl-5-cyano-4-methoxybenzoyl chloride
To 3-t-butyl-5-cyano-4-methoxybenzoic acid (586 mg), toluene (10
mL), N,N-dimethylformamide (2 droplets) and thionyl chloride (0.27
mL) was added, and the mixture was stirred at 60.degree. C. for 16
hours. The solvent was distilled off under reduced pressure and
then azeotroped with toluene to obtain the title compound (630 mg)
as a brown oily substance.
(g) Synthesis of
3-(3-t-butyl-5-cyano-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol
(943 mg) and 37% formalin (0.57 mL) in the same manner as in
Example 1 was dissolved in chloroform (15 mL), and triethylamine
(1.04 mL) and 3-t-butyl-5-cyano-4-methoxybenzoyl chloride (630 mg)
was added to the solution, and then the mixture was stirred at room
temperature for 1 hour. The solvent was distilled off under reduced
pressure and water was added, and then the mixture was extracted
with ethyl acetate. The organic layer was washed with 1N
hydrochloric acid, 1N sodium hydroxide and saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure and the obtained residue was purified by
silica gel column chromatography (n-hexane:ethyl acetate=6:1) to
obtain the title compound (904 mg) as a yellow oily substance.
(h) Synthesis of
3-(3-t-butyl-5-cyano-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothi-
azole
3-(3-t-butyl-5-cyano-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole
(452 mg) was dissolved in chloroform (9 mL), and 70%
metachloroperbenzoic acid (1.02 g) was added to the solution, and
then the mixture was stirred at room temperature for 16 hours and
quenched with 10% sodium thiosulfate. The solvent was distilled off
under reduced pressure and 1N sodium hydroxide was added, and then
the mixture was extracted with ethyl acetate. The organic layer was
washed with 1N sodium hydroxide and saturated brine, and then dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure to obtain the title compound (439 mg) as a pale
yellow oily substance.
1H-NMR.delta. (CDCl3): 1.36 (9H, s), 4.27 (3H, s), 4.93 (2H, s),
7.37 (1H, ddd, J=7.8, 7.1, 1.3 Hz), 7.58 (1H, ddd, J=8.2, 7.1, 1.3
Hz), 7.65 (1H, d, J=2.3 Hz), 7.70 (1H, d, J=2.3 Hz), 7.72 (1H, d,
J=2.3 Hz), 7.76-7.80 (1H, m).
(i) Synthesis of
3-(3-t-butyl-5-cyano-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothi-
azole
3-(3-t-butyl-5-cyano-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothi-
azole (364 mg) was dissolved in N,N-dimethylformamide (4 mL), and
lithium chloride (401 mg) was added to the solution, and then the
mixture was stirred at 120.degree. C. for 16 hours. To the reaction
solution, 1N hydrochloric acid was added, and then the mixture was
extracted with ethyl acetate. The organic layer was washed with 1N
hydrochloric acid and saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure and the obtained residue was crystallized from
n-hexane-ethyl acetate to obtain the title compound (299 mg) as a
colorless crystal.
1H-NMR.delta. (DMSO-d6): 1.37 (9H, s), 5.35 (2H, s), 7.43 (1H, dd,
J=7.4, 7.4 Hz), 7.73 (1H, d, J=2.1 Hz), 7.75 (1H, ddd, J=7.4, 7.4,
1.2 Hz), 7.88-7.93 (2H, m), 8.01 (1H, d, J=8.2 Hz), 11.23 (1H,
brs). MS (m/z): 369 (M-H)-.
Example 10
3-(3-cyano-4-hydroxy-5-isopropylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzoth-
iazole
(a) Synthesis of 5-bromo-2-hydroxy-3-isopropylbenzaldehyde
2-hydroxy-3-isopropylbenzaldehyde (20.19 g) was dissolved in
acetonitrile (160 mL), and N-bromosuccinimide (17.80 g) was added
to the solution at 0.degree. C., and then the mixture was stirred
at room temperature for 4 hours. The solvent was distilled off
under reduced pressure and water was added, and then the mixture
was extracted with ethyl acetate. The organic layer was washed with
saturated brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure to obtain the
title compound (25.88 g) as a yellow oily substance.
(b) Synthesis of 5-bromo-3-isopropyl-2-methoxybenzaldehyde
5-bromo-2-hydroxy-3-isopropylbenzaldehyde (25.88 g) was dissolved
in N,N-dimethylformamide (100 mL), and potassium carbonate (27.64
g) and dimethylsulfuric acid (9.5 mL) were added to the solution
under water cooling, and the mixture was stirred at room
temperature for 2 hours. Water was added to the reaction solution,
and then the reaction mixture was extracted with ethyl acetate. The
organic layer was washed with water and saturated brine, and then
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure to obtain the title compound (26.76 g) as a
brown oily substance.
(c) Synthesis of
5-bromo-1-diethoxymethyl-3-isopropyl-2-methoxybenzene
5-bromo-3-isopropyl-2-methoxybenzaldehyde (26.76 g) was dissolved
in n-hexane (50 mL) and triethyl orthoformate (22 mL), and
Amberlyst-15 (2.68 g) was added to the solution, and then the
mixture was refluxed for 4 hours. The reaction solution was
filtered, and then the solvent was distilled off under reduced
pressure to obtain the title compound (31.55 g) as a brown oily
substance.
(d) Synthesis of 3-formyl-5-isopropyl-4-methoxybenzoic acid
To magnesium (2.43 g), tetrahydrofuran (100 mL),
5-bromo-1-diethoxymethyl-3-isopropyl-2-methoxybenzene (31.55 g) and
a 0.97M methylmagnesium bromide-tetrahydrofuran solution (15 mL)
were added, and then the mixture was stirred at room temperature
for 2 hours. The reaction solution was cooled to 0.degree. C. and
stirred under a carbon dioxide atmosphere for 30 minutes, and then
2N hydrochloric acid (100 mL) was added and the reaction mixture
was stirred at room temperature for 16 hours. The organic solvent
was distilled off under reduced pressure, and then the mixture was
extracted with diisopropylether. The organic layer was extracted
with 1N sodium hydroxide (100 mL) added thereto, and then the
aqueous layer was washed twice with diisopropylether. The aqueous
layer was acidified with 4N hydrochloric acid added thereto, and
then extracted with ethyl acetate. The organic layer was washed
with saturated brine, and then dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure to obtain the
title compound (15.85 g) as a brown solid.
(e) Synthesis of 3-cyano-5-isopropyl-4-methoxybenzoic acid
3-formyl-5-isopropyl-4-methoxybenzoic acid (15.85 g) was dissolved
in formic acid (80 mL), and hydroxylamine hydrochloride (5.45 g)
was added to the solution, and the mixture was refluxed for 19
hours. The solvent was distilled off under reduced pressure and
water was added, and then the mixture was extracted with ethyl
acetate. The organic layer was washed with saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure to obtain the title compound (15.62 g)
as a brown solid.
1H-NMR.delta. (DMSO-d6): 1.21 (6H, d, J=6.9 Hz), 3.29 (1H, sevent,
J=6.9 Hz), 4.04 (3H, s), 8.10 (1H, s). MS (m/z): 218 (M-H)-.
(f) Synthesis of 3-cyano-5-isopropyl-4-methoxybenzoyl chloride
To 3-cyano-5-isopropyl-4-methoxybenzoic acid (658 mg), toluene (7
mL), N,N-dimethylformamide (2 droplets) and thionyl chloride (0.33
mL) were added, and the mixture was stirred at 60.degree. C. for 16
hours. The solvent was distilled off under reduced pressure and
then azeotroped with toluene to obtain the title compound (710 mg)
as a brown oily substance.
(g) Synthesis of
3-(3-cyano-5-isopropyl-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol
(1.25 g) and 37% formalin (0.83 mL) in the same manner as in
Example 1 was dissolved in chloroform (7 mL), and triethylamine
(1.25 mL) and 3-cyano-5-isopropyl-4-methoxybenzoyl chloride (710
mg) were added to the solution, and then the mixture was stirred at
room temperature for 2 hours. The solvent was distilled off under
reduced pressure and water was added, and then the mixture was
extracted with ethyl acetate. The organic layer was washed with 1N
hydrochloric acid, 1N sodium hydroxide and saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure and the obtained residue was purified by
silica gel column chromatography (n-hexane:ethyl acetate=6:1) to
obtain the title compound (1.02 g) as a yellow oily substance.
(h) Synthesis of
3-(3-cyano-5-isopropyl-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzot-
hiazole
3-(3-cyano-5-isopropyl-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole
(501 mg) was dissolved in chloroform (5 mL), and 70%
metachloroperbenzoic acid (996 mg) was added to the solution, and
then the mixture was stirred at room temperature for 18 hours and
quenched with 10% sodium thio sulfate. The solvent was distilled
off under reduced pressure and 1N sodium hydroxide was added, and
then the mixture was extracted with ethyl acetate. The organic
layer was washed with 1N sodium hydroxide and saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure and the obtained residue was purified by
silica gel column chromatography (n-hexane:ethyl acetate=3:1) to
obtain the title compound (439 mg) as a brown amorphous
product.
(i) Synthesis of
3-(3-cyano-4-hydroxy-5-isopropylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzot-
hiazole
3-(3-cyano-5-isopropyl-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzot-
hiazole (434 mg) was dissolved in N,N-dimethylformamide (5 mL), and
lithium chloride (496 mg) was added to the solution, and then the
mixture was stirred at 100.degree. C. for 20 hours. To the reaction
solution, 1N hydrochloric acid was added, and then the reaction
mixture was extracted with ethyl acetate. The organic layer was
washed with 1N hydrochloric acid and saturated brine, and then
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure and the obtained residue was crystallized
from n-hexane-chloroform to obtain the title compound (351 mg) as a
colorless crystal.
1H-NMR.delta. (DMSO-d6): 1.18 (6H, d, J=6.8 Hz), 3.35 (1H, sevent,
J=6.8 Hz), 5.34 (2H, s), 7.43 (1H, ddd, J=7.8, 7.8, 0.8 Hz), 7.75
(1H, ddd, J=8.4, 7.8, 1.3 Hz), 7.76 (1H, d, J=2.3 Hz), 7.87 (1H, d,
J=2.3 Hz), 7.90 (1H, dd, J=7.8, 0.8 Hz), 8.00 (1H, d, J=8.4 Hz). MS
(m/z): 355 (M-H)-.
Example 11
3-(3-cyano-5-cyclobutyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzot-
hiazole
(a) Synthesis of 1-cyclobutyl-2-methoxymethoxybenzene
2-cyclobutylphenol (871 mg) was dissolved in N,N-dimethylformamide
(5 mL), and 60% sodium hydride (1.30 g) was added to the solution
at 0.degree. C. After stirring the mixture for 30 minutes,
chloromethyl methyl ether (2.1 mL) was added and the mixture was
stirred for 14 hours. Water was added to the reaction solution, and
then the reaction mixture was extracted with ethyl acetate. The
organic layer was washed with water and saturated brine, and then
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure and the obtained residue was purified by
silica gel column chromatography (n-hexane:ethyl acetate=10:1) to
obtain the title compound (1.13 g) as a colorless oily
substance.
(b) Synthesis of 3-cyclobutyl-2-hydroxybenzaldehyde
1-cyclobutyl-2-methoxymethoxybenzene (1.18 g) was dissolved in
tetrahydrofuran (11 mL), and a 1.01M s-butyllithium-cyclohexane
solution (8.7 mL) was added to the solution at -60.degree. C. over
15 minutes under an argon gas flow, and then the mixture was
stirred for 2 hours. N,N-dimethylformamide (0.90 mL) was added and
the mixture was stirred at the same temperature for 2 hours. 4N
hydrochloric acid (15 mL) was added at room temperature, and then
the mixture was stirred at 60.degree. C. for 20 hours. The solvent
was distilled off under reduced pressure and water was added, and
then the mixture was extracted with ethyl acetate. The organic
layer was washed with saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure and the obtained residue was purified by silica
gel column chromatography (n-hexane:ethyl acetate=20:1) to obtain
the title compound (0.95 g) as a colorless oily substance.
(c) Synthesis of 5-bromo-3-cyclobutyl-2-hydroxybenzaldehyde
3-cyclobutyl-2-hydroxybenzaldehyde (2.29 g) was dissolved in
acetonitrile (30 mL), and N-bromosuccinimide (5.10 g) was added to
the solution at 0.degree. C., and then the mixture was stirred at
room temperature for 4 hours. The solvent was distilled off under
reduced pressure and water was added, and then the mixture was
extracted with ethyl acetate. The organic layer was washed with
water and saturated brine, and then dried over anhydrous sodium
sulfate. The solvent was distilled off under reduced pressure and
the obtained residue was used for the synthesis of (d).
(d) Synthesis of 5-bromo-3-cyclobutyl-2-methoxybenzaldehyde
5-bromo-3-cyclobutyl-2-hydroxybenzaldehyde was dissolved in
N,N-dimethylformamide (30 mL), and potassium carbonate (10.79 g)
and dimethylsulfuric acid (3.7 mL) were added to the solution under
water cooling, and then the mixture was stirred at room temperature
for 14 hours. The reaction solution was filtered and water was
added, and then the reaction mixture was extracted with ethyl
acetate. The organic layer was washed with saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure and the obtained residue was purified by
silica gel column chromatography (n-hexane:ethyl acetate=20:1) to
obtain the title compound (1.27 g) as a yellow oily substance.
(e) Synthesis of
5-bromo-3-cyclobutyl-1-diethoxymethyl-2-methoxybenzene
5-bromo-3-cyclobutyl-2-methoxybenzaldehyde (1.15 g) was dissolved
in n-hexane (5 mL) and triethyl orthoformate (0.93 mL), and
Amberlyst-15 (115 mg) was added to the solution, and then the
mixture was refluxed for 3 hours. The reaction solution was
filtered, and then the solvent was distilled off under reduced
pressure to obtain the title compound (1.33 g) as a yellow oily
substance.
(f) Synthesis of 3-cyclobutyl-5-formyl-4-methoxybenzoic acid
To magnesium (106 mg), tetrahydrofuran (3.5 mL),
5-bromo-3-cyclobutyl-1-diethoxymethyl-2-methoxybenzene (1.33 g) and
a 0.97M methylmagnesium bromide-tetrahydrofuran solution (1.32 mL)
was added, and then the mixture was stirred at room temperature for
1.5 hours. The reaction solution was cooled to 0.degree. C. and
stirred under a carbon dioxide atmosphere for 15 hours, and then 2N
hydrochloric acid (10 mL) was added and the mixture was stirred at
mom temperature for 1 hour. The organic solvent was distilled off
under reduced pressure and then extracted with diisopropylether.
The organic layer was extracted with 1N sodium hydroxide added
thereto, and then the aqueous layer was washed twice with
diisopropylether. The aqueous layer was acidified with 4N
hydrochloric acid added thereto, and then extracted with ethyl
acetate. The organic layer was washed with saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure to obtain the title compound (458 mg) as
a brown solid.
(g) Synthesis of 3-cyano-5-cyclobutyl-4-methoxybenzoic acid
3-cyclobutyl-5-formyl-4-methoxybenzoic acid (458 mg) was dissolved
in formic acid (2.5 mL), and hydroxylamine hydrochloride (163 mg)
was added to the solution, and then the mixture was refluxed for 19
hours. The solvent was distilled off under reduced pressure and
water was added, and then the mixture was extracted with ethyl
acetate. The organic layer was washed with saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure to obtain the title compound (404 mg) as
a brown solid.
1H-NMR.delta. (CDCl3): 1.82-2.48 (6H, m), 3.76 (1H, quint, J=8.7
Hz), 4.15 (3H, s), 8.18 (1H, d, J=2.2 Hz), 8.20 (1H, d, J=2.2 Hz).
MS (m/z): 230 (M-H)-.
(h) Synthesis of 3-cyano-5-cyclobutyl-4-methoxybenzoyl chloride
To 3-cyano-5-cyclobutyl-4-methoxybenzoic acid (190 mg), toluene
(2.0 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride
(0.07 mL) were added, and the mixture was stirred at 60.degree. C.
for 3 hours. The solvent was distilled off under reduced pressure
and then azeotroped with toluene to obtain the title compound (204
mg) as a brown oily substance.
(i) Synthesis of
3-(3-cyano-5-cyclobutyl-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol
(153 mg) and 37% formalin (0.10 mL) in the same manner as in
Example 1 was dissolved in dichloromethane (3 mL), and
triethylamine (0.34 mL) and 3-cyano-5-cyclobutyl-4-methoxybenzoyl
chloride (204 mg) were added to the solution, and then the mixture
was stirred at room temperature for 1 hour. The solvent was
distilled off under reduced pressure and water was added, and then
the mixture was extracted with ethyl acetate. The organic layer was
washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated
brine, and then dried over anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure and the obtained residue
was used for the synthesis of (j).
(j) Synthesis of
3-(3-cyano-5-cyclobutyl-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzo-
thiazole
3-(3-cyano-5-cyclobutyl-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole
was dissolved in dichloromethane (4 mL), and 70%
metachloroperbenzoic acid (1.62 g) was added to the solution. After
stirring the mixture at room temperature for 28 hours, 1N sodium
hydroxide was added and then the mixture was extracted with ethyl
acetate. The organic layer was washed with 1N sodium hydroxide and
saturated brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure to obtain the
title compound (156 mg) as a yellow solid.
(k) Synthesis of
3-(3-cyano-5-cyclobutyl-4-hydroxybenzoyl)-1,1-dioxo-2-dihydro-1,3-benzoth-
iazole
3-(5-cyano-3-cyclobutyl-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzo-
thiazole (150 mg) was dissolved in N,N-dimethylformamide (1.5 mL),
and lithium chloride (248 mg) was added to the solution, and then
the mixture was stirred at 120.degree. C. for 2.5 hours. To the
reaction solution, 1N hydrochloric acid was added, and then the
mixture was extracted with ethyl acetate. The organic layer was
washed with 1N hydrochloric acid and saturated brine, and then
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure and the obtained residue was crystallized
from n-hexane-chloroform to obtain the title compound (95 mg) as a
brown crystal.
1H-NMR.delta. (DMSO-d6): 1.72-2.18 (4H, m), 2.25-2.39 (2H, m), 3.77
(1H, quint, J=8.7 Hz), 5.35 (2H, s), 7.44 (1H, dd, J=7.6, 7.6 Hz),
7.77 (1H, dd, J=8.4, 7.6 Hz), 7.79 (1H, d, J=2.2 Hz), 7.87 (1H, d,
J=2.2 Hz), 7.91 (1H, d, J=7.6 Hz), 8.04 (1H, d, J=8.4 Hz). MS
(m/z): 367 (M-H)-.
Example 12
3-(3-cyano-5-ethyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazo-
le
(a) Synthesis of methyl 3-cyano-4-methoxy-5-trimethylsilanylethynyl
benzoate
Methyl 3-cyano-5-iodo-4-methoxybenzoate (2.13 g) was dissolved in
tetrahydrofuran (30 mL), and triethylamine (10 mL), copper iodide
(256 mg), tetrakistriphenylphosphine palladium (777 mg) and
trimethylsilylacetylene (858 mg) were added to the solution, and
then the mixture was stirred at room temperature for 1 hour. The
solvent was distilled off under reduced pressure and the obtained
residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=4:1) to obtain the title compound (2.03 g)
as a brown oily substance.
(b) Synthesis of methyl 3-cyano-5-ethynyl-4-methoxybenzoate
Methyl 3-cyano-4-methoxy-5-trimethylsilanylethynyl benzoate (2.03
g) was dissolved in tetrahydrofuran (20 mL), and an aqueous 1N
sodium hydroxide solution (8 mL) was added to the solution, and
then the mixture was stirred at room temperature for 10 minutes.
The solvent was distilled off under reduced pressure and 1N
hydrochloric acid was added, and the mixture was extracted with
ethyl acetate. The organic layer was washed with saturated brine,
and then dried over anhydrous sodium sulfate. The solvent was
distilled off under reduced pressure to obtain the title compound
(1.37 g) as a colorless crystal.
(c) Synthesis of methyl 3-cyano-5-ethyl-4-methoxybenzoate
Methyl 3-cyano-5-ethynyl-4-methoxybenzoate (475 mg) was dissolved
in tetrahydrofuran (10 mL), and 5% palladium-carbon (150 mg) was
added to the solution, and then the mixture was stirred under a
hydrogen atmosphere at room temperature for 30 minutes. The
reaction solution was filtered, and then the solvent was distilled
off under reduced pressure and the obtained residue was purified by
silica gel column chromatography (n-hexane:ethyl acetate=5:1) to
obtain the title compound (480 mg) as a colorless crystal.
(d) Synthesis of 3-cyano-5-ethyl-4-methoxybenzoic acid
Methyl 3-cyano-5-ethyl-4-methoxybenzoate (480 mg) was dissolved in
tetrahydrofuran (6 mL) and water (2 mL), and lithium hydroxide
monohydrate (370 mg) was added to the solution, and then the
mixture was stirred at room temperature for 5 hours. The solvent
was distilled off under reduced pressure and 1N hydrochloric acid
was added, and then the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine, and then dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure to obtain the title compound (403 mg) as a
colorless crystal.
1H-NMR.delta. (DMSO-d6): 1.50 (3H, t, J=7.5 Hz), 3.01 (2H, q, J=7.5
Hz), 4.36 (3H, s), 8.40 (1H, d, J=2.1 Hz), 8.41 (1H, d, J=2.1 Hz).
MS (m/z): 204 (M-H)-.
(e) Synthesis of 3-cyano-5-ethyl-4-methoxybenzoyl chloride
To 3-cyano-5-ethyl-4-methoxybenzoic acid (347 mg), toluene (3.5
mL), N,N-dimethylformamide (0.01 mL) and thionyl chloride (0.15 mL)
were added, and then the mixture was stirred at 60.degree. C. for
14 hours. The solvent was distilled off under reduced pressure and
then azeotroped with toluene to obtain the title compound (387 mg)
as a brown oily substance.
(f) Synthesis of
3-(3-cyano-5-ethyl-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol
(318 mg) and 37% formalin (0.21 mL) in the same manner as in
Example 1 was dissolved in dichloromethane (6 mL), and
triethylamine (0.71 mL) and 3-cyano-5-ethyl-4-methoxybenzoyl
chloride (387 mg) were added to the solution, and then the mixture
was stirred at room temperature for 1.5 hours. The solvent was
distilled off under reduced pressure and water was added, and then
the mixture was extracted with ethyl acetate. The organic layer was
washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated
brine, and then dried over anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure and the obtained residue
was purified by silica gel column chromatography (n-hexane:ethyl
acetate=6:1) to obtain the title compound (498 mg) as a yellow oily
substance.
(g) Synthesis of
3-(3-cyano-5-ethyl-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiaz-
ole
3-(3-cyano-5-ethyl-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole
(366 mg) was dissolved in dichloromethane (7 mL), and 70%
metachloroperbenzoic acid (1.20 g) was added to the solution. After
stirring the mixture at room temperature for 14 hours, 1N sodium
hydroxide was added and the mixture was extracted with ethyl
acetate. The organic layer was washed with 1N sodium hydroxide and
saturated brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure to obtain the
title compound (309 mg) as a colorless solid.
(h) Synthesis of
3-(3-cyano-5-ethyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiaz-
ole
3-(3-cyano-5-ethyl-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiaz-
ole (309 mg) was dissolved in N,N-dimethylformamide (3 mL), and
lithium chloride (443 mg) was added to the solution, and then the
mixture was stirred at 120.degree. C. for 2.5 hours. To the
reaction solution, 1N hydrochloric acid was added, and then the
mixture was extracted with ethyl acetate. The organic layer was
washed with 1N hydrochloric acid and saturated brine, and then
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure and the obtained residue was crystallized
from n-hexane-chloroform to obtain the title compound (257 mg) as a
brown crystal.
1H-NMR.delta. (DMSO-d6): 1.15 (3H, t, J=7.6 Hz), 2.68 (2H, q, J=7.6
Hz), 5.34 (2H, s), 7.43 (1H, dd, J=7.6, 7.6 Hz), 7.74 (1H, d, J=2.2
Hz), 7.75 (1H, dd, J=8.4, 7.6 Hz), 7.88 (1H, d, J=2.2 Hz), 7.90
(1H, d, J=7.6 Hz), 8.00 (1H, d, J=8.4 Hz), 11.01 (1H, brs). MS
(m/z): 341 (M-H)-.
Example 13
3-(3-cyano-5-cyclopropyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzo-
thiazole
(a) Synthesis of methyl 3-cyano-5-cyclopropyl-4-methoxybenzoate
Methyl 3-cyano-4-hydroxy-5-iodobenzoate (1.00 g) was dissolved in
1,4-dioxane (15 mL), and potassium carbonate (1.31 g),
cyclopropylboronic acid (325 mg) and
[1,3-bis-(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palla-
dium dichloride (108 mg) were added to the solution, and then the
mixture was stirred under an argon gas flow at 95.degree. C. for 22
hours. The reaction solution was filtered and the solvent was
distilled off under reduced pressure, and then the obtained residue
was purified by silica gel column chromatography (n-hexane:ethyl
acetate=4:1) to obtain the title compound (348 mg) as a pale yellow
crystal.
(b) Synthesis of 3-cyano-5-cyclopropyl-4-methoxybenzoic acid
Methyl 3-cyano-5-cyclopropyl-4-methoxybenzoate (491 mg) was
dissolved in tetrahydrofuran (7.5 mL) and water (2.5 mL), and
lithium hydroxide monohydrate (359 mg) was added to the solution,
and then the mixture was stirred at mom temperature for 20 hours.
The organic solvent was distilled off under reduced pressure and
the aqueous layer was washed with n-hexane. To the aqueous layer,
1N hydrochloric acid was added, and the mixture was extracted with
ethyl acetate under acidic conditions. The organic layer was washed
with saturated brine, and then dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure to obtain the
title compound (394 mg) as a pale brown crystal.
1H-NMR.delta. (DMSO-d6): 0.74-0.79 (2H, m), 1.03-1.10 (2H, m),
2.13-2.23 (1H, m), 4.06 (3H, s), 7.65 (1H, d, J=2.0 Hz), 8.04 (1H,
d, J=2.0 Hz). MS (m/z): 216 (M-H)-.
(c) Synthesis of 3-cyano-5-cyclopropyl-4-methoxybenzoyl
chloride
To 3-cyano-5-cyclopropyl-4-methoxybenzoic acid (200 mg), toluene (2
mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.10
mL) were added, and the mixture was stirred at 60.degree. C. for 16
hours. The solvent was distilled off under reduced pressure and the
obtained resiue was azeotroped with toluene and used for the
synthesis of (d).
(d) Synthesis of
3-(3-cyano-5-cyclopropyl-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol
(346 mg) and 37% formalin (0.23 mL) in the same manner as in
Example 1 was dissolved in chloroform (3 mL), and triethylamine
(0.38 mL) and 3-cyano-5-cyclopropyl-4-methoxybenzoyl chloride were
added to the solution, and then stirred at room temperature for 2
hours. The solvent was distilled off under reduced pressure and
water was added, and then the mixture was extracted with ethyl
acetate. The organic layer was washed with 1N hydrochloric acid, 1N
sodium hydroxide and saturated brine, and then dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure and the obtained residue was used for the synthesis of
(e).
(e) Synthesis of
3-(3-cyano-5-cyclopropyl-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benz-
othiazole
3-(3-cyano-5-cyclopropyl-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole
was dissolved in chloroform (5 mL), and 70% metachloroperbenzoic
acid (422 mg) was added to the solution, and then the mixture was
stirred at room temperature for 16 hours and quenched with 10%
sodium thiosulfate. The solvent was distilled off under reduced
pressure and 1N sodium hydroxide was added, and then the mixture
was extracted with ethyl acetate. The organic layer was washed with
1N sodium hydroxide and saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure and the obtained residue was crystallized from
n-hexane-ethyl acetate-methanol to obtain the title compound (147
mg) as a colorless crystal.
(f) Synthesis of
3-(3-cyano-5-cyclopropyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benz-
othiazole
3-(3-cyano-5-cyclopropyl-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benz-
othiazole (142 mg) was dissolved in N,N-dimethylformamide (2 mL),
and lithium chloride (163 mg) was added to the solution, and then
the mixture was stirred at 100.degree. C. for 23 hours. To the
reaction solution, 1N hydrochloric acid was added, and then the
mixture was extracted with ethyl acetate. The organic layer was
washed with 1N hydrochloric acid and saturated brine, and then
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure and the obtained residue was crystallized
from n-hexane-ethyl acetate to obtain the title compound (115 mg)
as a colorless crystal.
1H-NMR.delta. (DMSO-d6): 0.69-0.75 (2H, m), 0.94-1.01 (2H, m),
2.05-2.15 (1H, m), 5.30 (2H, s), 7.41 (1H, d, J=2.1 Hz), 7.43 (1H,
dd, J=7.8, 7.8 Hz), 7.75 (1H, ddd, J=8.4, 7.8, 1.2 Hz), 7.84 (1H,
d, J=2.1 Hz), 7.90 (1H, d, J=7.8 Hz), 8.02 (1H, d, J=8.4 Hz). MS
(m/z): 353 (M-H)-.
Example 14
3-(3-cyano-5-ethynyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothia-
zole
(a) Synthesis of 3-cyano-5-ethynyl-4-methoxybenzoic acid
Methyl 3-cyano-5-ethynyl-4-methoxybenzoate (640 mg) was dissolved
in tetrahydrofuran (6 mL) and water (3 mL), and lithium hydroxide
monohydrate (495 mg) was added to the solution, and then the
mixture was stirred at room temperature for 3 hours. The solvent
was distilled off under reduced pressure and 1N hydrochloric acid
was added, and then the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine, and then dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure to obtain the title compound (610 mg) as a brown
crystal.
1H-NMR.delta. (DMSO-d6): 4.20 (3H, s), 4.72 (1H, s), 8.17 (1H, d,
J=2.1 Hz), 8.24 (1H, d, J=2.1 Hz). MS (m/z): 200 (M-H)-.
(b) Synthesis of 3-cyano-5-ethynyl-4-methoxybenzoyl chloride
To 3-cyano-5-ethynyl-4-methoxybenzoic acid (610 mg), toluene (6
mL), N,N-dimethylformamide (1 droplet) and oxalyl chloride (0.32
mL) were added to the solution under ice cooling, and the mixture
was stirred at room temperature for 1.5 hours. The solvent was
distilled off under reduced pressure and the obtained residue was
azeotroped with toluene and used for the synthesis of (c).
(c) Synthesis of
3-(3-cyano-5-ethynyl-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol
(570 mg) and 37% formalin (0.38 mL) in the same manner as in
Example 1 was dissolved in dichloromethane (10 mL), and
triethylamine (1.2 mL) and 3-cyano-5-ethynyl-4-methoxybenzoyl
chloride were added to the solution, and then the mixture was
stirred at mom temperature for 2.5 hours. The solvent was distilled
off under reduced pressure and water was added, and then the
mixture was extracted with ethyl acetate. The organic layer was
washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated
brine, and then dried over anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure and the obtained residue
was purified by silica gel column chromatography (n-hexane:ethyl
acetate=5:1) to obtain the title compound (283 mg) as a yellow oily
substance.
(d) Synthesis of
3-(3-cyano-5-ethynyl-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothi-
azole
3-(3-cyano-5-ethynyl-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole
(344 mg) was dissolved in dichloromethane (5 mL), and 70%
metachloroperbenzoic acid (1.94 g) was added to the solution. After
stirring the mixture at room temperature for 16 hours, 1N sodium
hydroxide was added, and then the mixture was extracted with ethyl
acetate. The organic layer was washed with 1N sodium hydroxide and
saturated brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure to obtain the
title compound (199 mg) as a yellow oily substance.
(e) Synthesis of
3-(3-cyano-5-ethynyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothi-
azole
3-(3-cyano-5-ethynyl-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothi-
azole (197 mg) was dissolved in N,N-dimethylformamide (2 mL), and
lithium chloride (239 mg) was added to the solution, and then the
mixture was stirred at 100.degree. C. for 1 hour. To the reaction
solution, 1N hydrochloric acid was added, and then the mixture was
extracted with ethyl acetate. The organic layer was washed with 1N
hydrochloric acid and saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure and the obtained residue was purified by silica
gel column chromatography (n-hexane:ethyl acetate=1:1), and then
crystallized from n-hexane-acetone to obtain the title compound
(102 mg) as a pale yellow crystal.
1H-NMR.delta. (DMSO-d6): 4.58 (1H, s), 5.35 (2H, s), 7.44 (1H, dd,
J=7.6, 7.6 Hz), 7.76 (1H, dd, J=8.4, 7.6 Hz), 7.91 (1H, d, J=8.4
Hz), 7.93 (1H, d, J=2.4 Hz), 8.04 (1H, d, J=2.4 Hz), 8.05 (1H, d,
J=7.6 Hz). MS (m/z): 337 (M-H)-.
Example 15
3-(3-cyano-4-hydroxy-5-methylsulfanylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-be-
nzothiazole
(a) Synthesis of methyl 3-bromo-4-hydroxybenzoate
Methyl 4-hydroxybenzoate (25.00 g) was dissolved in chloroform (225
mL) and methanol (25 mL), and a chloroform (30 mL) solution of
bromine (8.5 mL) was added dropwise to the solution, and then the
mixture was stirred for 2 hours. The reaction solution was diluted
with chloroform, washed with water, an aqueous 10% sodium
thiosulfate solution and saturated brine and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure to obtain the title compound (37.81 g) as a
colorless crystal.
(b) Synthesis of methyl 3-cyano-4-hydroxybenzoate
Methyl 3-bromo-4-hydroxybenzoate (37.81 g) was dissolved in
N,N-dimethylformamide (250 mL), and copper cyanide (22.03 g) was
added to the solution. After stirring the mixture at 150.degree. C.
for 16 hours, potassium carbonate (68.00 g) and chloromethyl methyl
ether (14.8 mL) were added to the solution under ice cooling, and
then the mixture was stirred for 2 hours. The reaction solution was
filtered and water was added, and then the reaction mixture was
extracted with ethyl acetate. After the operation of adding water
to the organic layer, stirring the mixture, filtering the mixture
and separating the organic layer was repeated three times, the
organic layer was washed with saturated brine and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure and the obtained residue was dissolved in
chloroform (30 mL). Trifluoroacetic acid (30 mL) was added to the
solution, and then the mixture was stirred at room temperature for
2 hours. The solvent was distilled off under reduced pressure and
the obtained residue was washed with a mixture of n-hexane and
ethyl acetate in a mixing ratio of 2:1 to obtain the title compound
(6.53 g) as a pale yellow crystal.
(c) Synthesis of methyl 3-cyano-4-hydroxy-5-iodobenzoate
Methyl 3-cyano-4-hydroxybenzoate (6.47 g) was dissolved in
chloroform (80 mL) and methanol (10 mL), and N-iodosuccinimide
(8.63 g) and trifluoromethanesulfonic acid (2.5 mL) were added to
the solution, and then the mixture was stirred at room temperature
for 1 hour. The solvent was distilled off under reduced pressure
and the obtained residue was washed with water to obtain the title
compound (11.29 g) as a pale yellow crystal.
(d) Synthesis of methyl 3-cyano-5-iodo-4-methoxybenzoate
Methyl 3-cyano-4-hydroxy-5-iodobenzoate (11.29 g) was dissolved in
N,N-dimethylformamide (230 mL), and potassium carbonate (49.20 g)
and dimethylsulfuric acid (17.0 mL) were added to the solution, and
then the mixture was stirred at room temperature for 18 hours.
After the reaction solution was filtered, water was added and the
precipitated crystal was collected by filtration to obtain the
title compound (8.99 g) as a pale yellow crystal.
(e) Synthesis of 3-cyano-5-iodo-4-methoxybenzoic acid
Methyl 3-cyano-5-iodo-4-methoxybenzoate (8.00 g) was dissolved in
tetrahydrofuran (100 mL) and water (50 mL), and lithium hydroxide
monohydrate (423 g) was added to the solution, and then the mixture
was stirred at room temperature for 4 hours. The organic solvent
was distilled off under reduced pressure and the aqueous layer was
washed with n-hexane. The aqueous layer was acidified with 2N
hydrochloric acid and then extracted with ethyl acetate. The
organic layer was washed with saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure to obtain the title compound (7.26 g) as a
colorless crystal.
1H-NMR.delta. (DMSO-d6): 4.38 (3H, s), 8.58 (1H, d, J=2.0 Hz), 8.86
(1H, d, J=2.0 Hz), 13.89 (1H, brs). MS (m/z): 302 (M-1)-.
(f) Synthesis of 3-cyano-5-iodo-4-methoxybenzoyl chloride
To 3-cyano-5-iodo-4-methoxybenzoic acid (512 mg), toluene (5 mL),
N,N-dimethylformamide (1 droplet) and thionyl chloride (0.15 mL)
were added, and the mixture was stirred at 60.degree. C. for 15
hours. The solvent was distilled off under reduced pressure and
then azeotroped with toluene to obtain the title compound (527 mg)
as a pale yellow solid.
(g) Synthesis of
3-(3-cyano-5-iodo-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol
(317 mg) and 37% formalin (0.21 mL) in the same manner as in
Example 1 was dissolved in dichloromethane (6 mL), and
triethylamine (0.70 mL) and 3-cyano-5-iodo-4-methoxybenzoyl
chloride (527 mg) were added to the solution, and then the mixture
was stirred at room temperature for 14 hours. The solvent was
distilled off under reduced pressure and water was added, and then
the mixture was extracted with ethyl acetate. The organic layer was
washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated
brine, and then dried over anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure and the obtained residue
was purified by silica gel column chromatography (n-hexane:ethyl
acetate=5:1) to obtain the title compound (435 mg) as a yellow oily
substance.
(h) Synthesis of
3-(3-cyano-5-iodo-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazo-
le
3-(3-cyano-5-iodo-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole
(196 mg) was dissolved in dichloromethane (4 mL), and 70%
metachloroperbenzoic acid (495 mg) was added to the solution. After
stirring the mixture at room temperature for 2 hours, 1N sodium
hydroxide was added, and then the mixture was extracted with ethyl
acetate. The organic layer was washed with 1N sodium hydroxide and
saturated brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure and then the
obtained residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=2:1) to obtain the title compound (106 mg)
as a pale yellow oily substance.
(i) Synthesis of
3-(3-cyano-4-hydroxy-5-iodobenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazo-
le
3-(3-cyano-5-iodo-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazo-
le (106 mg) was dissolved in N,N-dimethylformamide (1 mL), and
lithium chloride (40 mg) was added to the solution, and then the
mixture was stirred at 100.degree. C. for 2 hours. To the reaction
solution, 1N hydrochloric acid was added, and then the mixture was
extracted with ethyl acetate. The organic layer was washed with 1N
hydrochloric acid and saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure to obtain the title compound (100 mg) as a yellow
oily substance.
1H-NMR.delta. (DMSO-d6): 5.35 (2H, s), 7.43 (1H, dd, J=7.8, 7.3
Hz), 7.76 (1H, dd, J=8.4, 7.3 Hz), 7.90 (1H, d, J=7.8 Hz), 8.02
(1H, d, J=2.2 Hz), 8.04 (1H, d, J=8.4 Hz), 827 (1H, d, J=2.2
Hz).
(j) Synthesis of
3-(3-cyano-4-methoxy-5-methylsulfanylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-b-
enzothiazole
3-(3-cyano-4-hydroxy-5-iodobenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazo-
le (334 mg) was dissolved in N,N-dimethylformamide (3.5 mL), and
2,2'-bipyridine (11 mg), zinc powder (95 mg), nickel bromide (16
mg) and dimethyl disulfide (0.04 mL) were added to the solution,
and then the mixture was stirred at 80.degree. C. for 1 hour. After
the reaction solution was filtered, 1N hydrochloric acid was added
and the reaction mixture was extracted with ethyl acetate. The
organic layer was washed with saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure and the obtained residue was dissolved in
N,N-dimethylformamide (3 mL). Potassium carbonate (298 mg) and
dimethylsulfuric acid (0.13 mL) was added to the solution, and then
the mixture was stirred at room temperature for 1 hour. Water was
added to the reaction solution, and then the reaction mixture was
extracted with ethyl acetate. The organic layer was washed with
water and saturated brine, and then dried over anhydrous sodium
sulfate. The solvent was distilled off under reduced pressure and
the obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=2:1) to obtain the title
compound (142 mg) as a pale yellow oily substance.
(k) Synthesis of
3-(3-cyano-4-hydroxy-5-methylsulfanylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-b-
enzothiazole
3-(3-cyano-4-methoxy-5-methylsulfanylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-b-
enzothiazole (142 mg) was dissolved in N,N-dimethylformamide (1
mL), and lithium chloride (64 mg) was added to the solution, and
then the mixture was stirred at 100.degree. C. for 1.5 hours. To
the reaction solution, 1N hydrochloric acid was added, and then the
mixture was extracted with ethyl acetate. The organic layer was
washed with 1N hydrochloric acid and saturated brine, and then
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure and the obtained residue was crystallized
from n-hexane-chloroform to obtain the title compound (95 mg) as a
yellow crystal.
1H-NMR.delta. (DMSO-d6): 2.46 (3H, s), 5.34 (2H, s), 7.45 (1H, dd,
J=7.6, 7.3 Hz), 7.68 (1H, d, J=2.2 Hz), 7.77 (1H, dd, J=8.4, 7.6
Hz), 7.82 (1H, d, J=2.2 Hz), 7.91 (1H, d, J=7.3 Hz), 8.08 (1H, d,
J=8.4 Hz). MS (m/z): 359 (M-H)-.
Example 16
3-(3-cyano-4-hydroxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-be-
nzothiazole
(a) Synthesis of
3-(3-cyano-4-methoxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-b-
enzothiazole
3-(3-cyano-4-methoxy-5-methylsulfanylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-b-
enzothiazole (163 mg) was dissolved in dichloromethane (4 mL), and
70% metachloroperbenzoic acid (480 mg) was added to the solution.
After stirring the mixture at room temperature for 18 hours, 1N
sodium hydroxide was added to the solution and then the mixture was
extracted with ethyl acetate. The organic layer was washed with 1N
sodium hydroxide and saturated brine, and then dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure to obtain the title compound (142 mg) as a pale yellow
solid.
(b) Synthesis of
3-(3-cyano-4-hydroxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-b-
enzothiazole
3-(3-cyano-4-methoxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-b-
enzothiazole (138 mg) was dissolved in N,N-dimethylformamide (1
mL), and lithium chloride (58 mg) was added to the solution, and
then the mixture was stirred at 70.degree. C. for 3 hours. To the
reaction solution, 1N hydrochloric acid was added, and then the
mixture was extracted with ethyl acetate. The organic layer was
washed with 1N hydrochloric acid and saturated brine, and then
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure and the obtained residue was crystallized
from n-hexane-chloroform to obtain the title compound (69 mg) as a
brown crystal.
1H-NMR.delta. (DMSO-d6): 3.26 (3H, s), 5.36 (2H, s), 7.40 (1H, dd,
J=7.6 Hz, 7.6 Hz), 7.73 (1H, dd, J=8.1, 7.6 Hz), 7.88 (1H, d, J=8.1
Hz), 7.92 (1H, d, J=7.6 Hz), 8.11 (2H, s). MS (m/z): 391
(M-H)-.
Example 17
3-(3-cyano-4-hydroxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-be-
nzothiazole
3-(3-cyano-4-hydroxy-5-methylsulfanylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-b-
enzothiazole (7 mg) was dissolved in tetrahydrofuran (0.5 mL) and
water (0.5 mL), and oxone (6 mg) was added to the solution, and
then the mixture was stirred at room temperature for 1 hour. To the
reaction solution, 1N hydrochloric acid was added, and then the
mixture was extracted with ethyl acetate. The organic layer was
washed with water and saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure and the obtained residue was crystallized from
n-hexane-chloroform to obtain the title compound (6 mg) as a pale
yellow crystal.
1H-NMR.delta. (CDCl3): 2.88 (3H, s), 4.96 (2H, s), 7.33 (1H, dd,
J=7.6, 7.4 Hz), 7.57 (1H, dd, J=8.0, 7.4 Hz), 7.67 (1H, d, J=8.0
Hz), 7.72 (1H, d, J=7.6 Hz), 7.89 (1H, s), 7.94 (1H, s). MS (m/z):
375 (M-H)-.
Example 18
3-(3-chloro-4-hydroxy-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3--
benzothiazole
(a) Synthesis of methyl 3-chloro-4-hydroxy-5-trifluoromethyl
benzoate
Methyl 4-hydroxy-3-trifluoromethyl benzoate (1.40 g) was dissolved
in chloroform (14 mL) and methanol (3 mL), and N-chlorosuccinimide
(1.70 g) and trifluoromethanesulfonic acid (40 .mu.L) were added to
the solution, and then the mixture was stirred at room temperature
for 16 hours. The solvent was distilled off under reduced pressure
and 10% sodium thiosulfate was added, and then the mixture was
extracted with ethyl acetate. The organic layer was washed with
water and saturated brine, and then dried over anhydrous sodium
sulfate. The solvent was distilled off under reduced pressure to
obtain the title compound (1.26 g) as a brown solid.
(b) Synthesis of methyl 3-chloro-4-methoxy-5-trifluoromethyl
benzoate
Methyl 3-chloro-4-hydroxy-5-trifluoromethyl benzoate (1.26 g) was
dissolved in N,N-dimethylformamide (6 mL), and potassium carbonate
(3.42 g) and dimethylsulfuric acid (1.40 mL) were added to the
solution, and then the mixture was stirred at room temperature for
2 hours. Water was added to the reaction solution, and then the
reaction mixture was extracted with ethyl acetate. The organic
layer was washed with saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure and the obtained residue was purified by silica
gel column chromatography (n-hexane:ethyl acetate=6:1) to obtain
the title compound (639 mg) as a colorless oily substance.
(c) Synthesis of 3-chloro-4-methoxy-5-trifluoromethylbenzoic
acid
Methyl 3-chloro-4-methoxy-5-trifluoromethyl benzoate (634 mg) was
dissolved in tetrahydrofuran (4 mL) and water (4 mL), and lithium
hydroxide monohydrate (396 mg) was added to the solution, and then
the mixture was stirred at room temperature for 2 hours. The
organic solvent was distilled off under reduced pressure and then
the aqueous layer was washed with n-hexane. The aqueous layer was
acidified with 1N hydrochloric acid and then extracted with ethyl
acetate. The organic layer was washed with saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure to obtain the title compound (579 mg) as
a colorless crystal.
1H-NMR.delta. (DMSO-d6): 3.97 (3H, s), 8.08 (1H, d, J=2.1 Hz), 8.26
(1H, d, J=2.1 Hz), 13.69 (1H, br). MS (m/z): 253 (M-H)-, 255
(M+2-H)-.
(d) Synthesis of 3-chloro-4-methoxy-5-trifluoromethylbenzoyl
chloride
To 3-chloro-4-methoxy-5-trifluoromethylbenzoic acid (300 mg),
toluene (3 mL), N,N-dimethylformamide (1 droplet) and thionyl
chloride (0.13 mL) were added, and the mixture was stirred at
60.degree. C. for 16 hours. The solvent was distilled off under
reduced pressure and the obtained residue was azeotroped with
toluene and used for the synthesis of (e).
(e) Synthesis of
3-(3-chloro-4-methoxy-5-trifluoromethylbenzoyl)-2,3-dihydro-1,3-benzothia-
zole
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol
(442 mg) and 37% formalin (0.29 mL) in the same manner as in
Example 1 was dissolved in chloroform (8 mL), and triethylamine
(0.49 mL) and 3-chloro-4-methoxy-5-trifluoromethylbenzoyl chloride
were added to the solution, and then the mixture was stirred at
room temperature for 1 hour. The solvent was distilled off under
reduced pressure and water was added, and then the mixture was
extracted with ethyl acetate. The organic layer was washed with 1N
hydrochloric acid, 1N sodium hydroxide and saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure and the obtained residue was used for
the synthesis of (f).
(f) Synthesis of
3-(3-chloro-4-methoxy-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-
-benzothiazole
3-(3-chloro-4-methoxy-5-trifluoromethylbenzoyl)-2,3-dthydro-1,3-benzothia-
zole was dissolved in chloroform (5 mL), and 70%
metachloroperbenzoic acid (726 mg) was added to the solution, and
then the mixture was stirred at room temperature for 18 hours and
quenched with 10% sodium thiosulfate. The solvent was distilled off
under reduced pressure and 1N sodium hydroxide was added, and then
the mixture was extracted with ethyl acetate. The organic layer was
washed with 1N sodium hydroxide and saturated brine, and then dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure and the obtained residue was purified by silica
gel column chromatography (n-hexane:ethyl acetate=3:1) to obtain
the title compound (74 mg) as a colorless crystal.
(g) Synthesis of
3-(3-chloro-4-hydroxy-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-
-benzothiazole
3-(3-chloro-4-methoxy-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-
-benzothiazole (74 mg) was dissolved in N,N-dimethylformamide (2
mL), lithium chloride (77 mg) was added to the solution, and then
the mixture was stirred at 70.degree. C. for 22 hours. To the
reaction solution, 1N hydrochloric acid was added, and then the
mixture was extracted with ethyl acetate. The organic layer was
washed with 1N hydrochloric acid and saturated brine, and then
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure and the obtained residue was crystallized
from diethylether to obtain the title compound (65 mg) as a
colorless crystal.
1H-NMR.delta. (DMSO-d6): 5.36 (2H, s), 7.44 (1H, ddd, J=7.8, 7.8,
0.8 Hz), 7.77 (1H, ddd, J=8.2, 7.8, 1.3 Hz), 7.86 (1H, d, J=2.1
Hz), 7.91 (1H, dd, J=7.8, 0.8 Hz), 8.06 (1H, d, J=2.1 Hz), 8.07
(1H, d, J=8.2 Hz). MS (m/z): 390 (M-H)-.
Example 19
3-(3-chloro-5-fluoro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothia-
zole
(a) Synthesis of 3-chloro-5-fluoro-4-methoxybenzoyl chloride
To 3-chloro-5-fluoro-4-methoxybenzoic acid (295 mg), toluene (3
mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.15
mL) were added, and then the mixture was stirred at 60.degree. C.
for 16 hours. The solvent was distilled off under reduced pressure
and the obtained residue was azeotroped with toluene and used for
the synthesis of (b).
(b) Synthesis of
3-(3-chloro-5-fluoro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol
(346 mg) and 37% formalin (0.23 mL) in the same manner as in
Example 1 was dissolved in chloroform (3 mL), and triethylamine
(0.38 mL) and 3-chloro-5-fluoro-4-methoxybenzoyl chloride were
added to the solution, and then the mixture was stirred at room
temperature for 90 minutes. The solvent was distilled off under
reduced pressure and water was added, and then the mixture was
extracted with ethyl acetate. The organic layer was washed with 1N
hydrochloric acid, 1N sodium hydroxide and saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure and the obtained residue was purified by
silica gel column chromatography (n-hexane:ethyl acetate=8:1) to
obtain the title compound (356 mg) as a pale yellow oily
substance.
(c) Synthesis of
3-(3-chloro-5-fluoro-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothi-
azole
3-(3-chloro-5-fluoro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole
(348 mg) was dissolved in chloroform (7 mL), and 70%
metachloroperbenzoic acid (739 mg) was added to the solution, and
then the mixture was stirred at room temperature for 16 hours and
quenched with 10% sodium thio sulfate. The solvent was distilled
off under reduced pressure and 1N sodium hydroxide was added, and
then the mixture was extracted with ethyl acetate. The organic
layer was washed with 1N sodium hydroxide and saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure to obtain the title compound (313 mg) as
a colorless crystal.
(d) Synthesis of
3-(3-chloro-5-fluoro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothi-
azole
3-(3-chloro-5-fluoro-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothi-
azole (307 mg) was dissolved in N,N-dimethylformamide (6 mL), and
lithium chloride (163 mg) was added to the solution, and then the
mixture was stirred at 100.degree. C. for 16 hours. To the reaction
solution, 1N hydrochloric acid was added, and then the mixture was
extracted with ethyl acetate. The organic layer was washed with 1N
hydrochloric acid and saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure and the obtained residue was purified by silica
gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain
the title compound (296 mg) as a pale yellow amorphous product.
1H-NMR.delta. (DMSO-d6): 5.35 (2H, s), 7.43 (1H, dd, J=7.4, 7.4
Hz), 3.59 (1H, dd, J=11.1, 1.8 Hz), 7.61 (1H, s), 7.76 (1H, ddd,
J=8.4, 7.4, 1.2 Hz), 7.90 (1H, d, J=7.4 Hz), 8.02 (1H, d, J=8.4
Hz), 11.35 (1H, brs). MS (m/z): 340 (M-H)-, 342 (M+2-H)-.
Example 20
3-(3,5-difluoro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole
(a) Synthesis of 3,5-difluoro-4-methoxybenzoyl chloride
To 3,5-difluoro-4-methoxybenzoic acid (310 mg), toluene (3 mL),
N,N-dimethylformamide (1 droplet) and thionyl chloride (0.14 mL)
were added to the solution, and then the mixture was stirred at
60.degree. C. for 16 hours. The solvent was distilled off under
reduced pressure and then azeotroped with toluene to obtain the
title compound (347 mg) as a brown oily substance.
(b) Synthesis of
3-(3,5-difluoro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol
(316 mg) and 37% formalin (0.21 mL) in the same manner as in
Example 1 was dissolved in dichloromethane (3 mL), and
diisopropylethylamine (0.56 mL) and 3,5-difluoro-4-methoxybenzoyl
chloride (347 mg) were added to the solution, and then the mixture
was stirred at room temperature for 1 hour. The solvent was
distilled off under reduced pressure and water was added, and then
the mixture was extracted with ethyl acetate. The organic layer was
washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated
brine, and then dried over anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure and the obtained residue
was used for the synthesis of (c).
(c) Synthesis of
3-(3,5-difluoro-4-methoxybenzoyl)-2,3-dihydro-1,1-dioxo-1,3-benzothiazole
3-(3,5-difluoro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole was
dissolved in dichloromethane (8 mL), and 70% metachloroperbenzoic
acid (2.01 g) was added to the solution. After stirring the mixture
at room temperature for 5 hours, 1N sodium hydroxide was added and
the mixture was extracted with ethyl acetate. The organic layer was
washed with 1N sodium hydroxide and saturated brine, and then dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure to obtain the title compound (453 mg) as a
colorless solid.
(d) Synthesis of
3-(3,5-difluoro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole
3-(3,5-difluoro-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole
(453 mg) was dissolved in N,N-dimethylformamide (4 mL), and lithium
chloride (559 mg) was added to the solution, and then the mixture
was stirred at 100.degree. C. for 16 hours. To the reaction
solution, 1N hydrochloric acid was added, and then the mixture was
extracted with ethyl acetate. The organic layer was washed with
water and saturated brine, and then dried over anhydrous sodium
sulfate. The solvent was distilled off under reduced pressure and
the obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=1:1) and then crystallized
from diethyl ether to obtain the title compound (270 mg) as a
colorless crystal.
1H-NMR.delta. (CD3OD): 5.14 (2H, s), 7.32 (2H, d, J=8.3 Hz), 7.40
(1H, dd, J=7.8, 7.3 Hz), 7.66 (1H, dd, J=8.4, 7.3 Hz), 7.77 (1H, d,
J=7.8 Hz), 7.83 (1H, d, J=8.4 Hz). MS (m/z): 324 (M-H)-.
Example 21
3-(3-chloro-4-hydroxy-5-methylsulfanylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-b-
enzothiazole
(a) Synthesis of methyl 3-chloro-4-hydroxy-5-iodobenzoate
Methyl 3-chloro-4-hydroxybenzoate (12.31 g) was dissolved in
dichloromethane (100 mL) and methanol (12 mL), and
N-iodosuccinimide (15.59 g) and trifluoromethanesulfonic acid (2
mL) were added to the solution, and then the mixture was stirred at
room temperature for 2 hours. The solvent was distilled off under
reduced pressure and the obtained residue was'washed with water
(100 mL) to obtain the title compound (20.52 g) as a colorless
crystal.
(b) Synthesis of methyl 3-chloro-5-iodo-4-methoxybenzoate
Methyl 3-chloro-4-hydroxy-5-iodobenzoate (3.00 g) was dissolved in
N,N-dimethylformamide (20 mL), and potassium carbonate (3.98 g) and
dimethylsulfuric acid (1.82 mL) were added to the solution, and
then the mixture was stirred at room temperature for 5 hours. The
reaction solution was filtered and water was added, and then the
reaction mixture was extracted with ethyl acetate. The organic
layer was washed with water and saturated brine, and then dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure to obtain the title compound (2.96 g) as a pale
yellow crystal.
(c) Synthesis of 3-chloro-5-iodo-4-methoxybenzoic acid
Methyl 3-chloro-5-iodo-4-methoxybenzoate (2.96 g) was dissolved in
tetrahydrofuran (23 mL) and water (7 mL), and lithium hydroxide
monohydrate (1.52 g) was added to the solution, and then the
mixture was stirred at room temperature for 19 hours. After the
organic solvent was distilled off, the mixture was acidified with
1N hydrochloric acid and extracted with ethyl acetate. The organic
layer was washed with saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure to obtain the title compound (2.74 g) as a
colorless crystal.
1H-NMR.delta. (CDCl3): 3.95 (3H, s), 8.11 (1H, dd, J=2.2 Hz, 0.5
Hz), 8.42 (1H, dd, J=2.2 Hz, 0.5 Hz). MS (m/z): 311 (M-H)-.
(d) Synthesis of 3-chloro-5-iodo-4-methoxybenzoyl chloride
To 3-chloro-5-iodo-4-methoxybenzoic acid (2.74 g), toluene (27 mL),
N,N-dimethylformamide (1 droplet) and thionyl chloride (0.76 mL)
were added to the solution, and then the mixture was stirred at
60.degree. C. for 15 hours. The solvent was distilled off under
reduced pressure and then azeotroped with toluene to obtain the
title compound (3.05 g) as a yellow solid.
(e) Synthesis of
3-(3-chloro-5-iodo-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol
(1.65 g) and 37% formalin (1.09 mL) in the same manner as in
Example 1 was dissolved in dichloromethane (15 mL), and
diisopropylethylamine (3.0 mL) and 3-chloro-5-iodo-4-methoxybenzoyl
chloride (3.05 g) were added to the solution, and then the mixture
was stirred at room temperature for 1 hour. The solvent was
distilled off under reduced pressure and water was added, and then
the mixture was extracted with ethyl acetate. The organic layer was
washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated
brine, and then dried over anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure and the obtained residue
was crystallized from a mixture of n-hexane and ethyl acetate in a
mixing ratio of 1:1 to obtain the title compound (2.44 g) as a pale
yellow solid.
(f) Synthesis of
3-(3-chloro-5-iodo-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiaz-
ole
3-(3-chloro-5-iodo-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole
(200 mg) was dissolved in tetrahydrofuran (5 mL), and 70%
metachloroperbenzoic acid (462 mg) was added to the solution. After
stirring the mixture at room temperature for 1.5 hours, 1N sodium
hydroxide was added and then the mixture was extracted with ethyl
acetate. The organic layer was washed with 1N sodium hydroxide and
saturated brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure to obtain the
title compound (96 mg) as a colorless oily substance.
(g) Synthesis of
3-(3-chloro-4-hydroxy-5-iodobenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiaz-
ole
3-(3-chloro-5-iodo-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiaz-
ole (922 mg) was dissolved in N,N-dimethylformamide (6 mL), and
lithium chloride (421 mg) was added to the solution, and then the
mixture was stirred at 120.degree. C. for 2.5 hours. To the
reaction solution, 1N hydrochloric acid was added, and then the
mixture was extracted with ethyl acetate. The organic layer was
washed with 1N hydrochloric acid and saturated brine, and then
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure to obtain the title compound (1.19 g) as a
brown oily substance.
1H-NMR.delta. (CDCl3): 4.98 (2H, s), 7.30-7.92 (6H, m).
(h) Synthesis of
3-(3-chloro-4-methoxy-5-methylsulfanylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3--
benzothiazole
3-(3-chloro-4-hydroxy-5-iodobenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiaz-
ole (1.19 g) was dissolved in N,N-dimethylformamide (9 mL), and
2,2'-bipyridine (32 mg), a zinc powder (262 mg), nickel bromide (45
mg) and dimethyl disulfide (0.09 mL) were added to the solution,
and then the mixture was stirred at 80.degree. C. for 1.5 hours.
After the reaction solution was filtered, 1N hydrochloric acid was
added and the reaction mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine, and then dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure and the obtained residue was dissolved in
N,N-dimethylformamide (6 mL). Potassium carbonate (828 mg) and
dimethylsulfuric acid (0.38 mL) was added to the solution, and then
the mixture was stirred at room temperature for 14 hours. Water was
added to the reaction solution, and then the reaction mixture was
extracted with ethyl acetate. The organic layer was washed with
saturated brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure and the obtained
residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=3:1) to obtain the title compound (203 mg)
as a yellow crystal.
(i) Synthesis of
3-(3-chloro-4-hydroxy-5-methylsulfanylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3--
benzothiazole
3-(3-chloro-4-methoxy-5-methylsulfanylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3--
benzothiazole (203 mg) was dissolved in N,N-dimethylformamide (2
mL), and lithium chloride (258 mg) was added to the solution, and
then the mixture was stirred at 120.degree. C. for 20 hours. To the
reaction solution, 1N hydrochloric acid was added, and then the
mixture was extracted with ethyl acetate. The organic layer was
washed with 1N hydrochloric acid and saturated brine, and then
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure and the obtained residue was crystallized
from n-hexane-diethylether to obtain the title compound (169 mg) as
a brown crystal.
1H-NMR.delta. (DMSO-d6): 2.44 (3H, s), 5.34 (2H, s), 7.38 (1H, s),
7.43 (1H, dd, J=7.8, 7.6 Hz), 7.54 (1H, s), 7.76 (1H, dd, J=8.6,
7.8 Hz), 7.90 (1H, d, J=7.6 Hz), 8.02 (1H, d, J=8.6 Hz), 10.54 (1H,
s). MS (m/z): 368 (M-H)-.
Example 22
3-(3-chloro-4-hydroxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-b-
enzothiazole
(a) Synthesis of
3-(3-chloro-4-methoxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3--
benzothiazole
3-(3-chloro-4-methoxy-5-methylsulfanylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3--
benzothiazole (828 mg) was dissolved in dichloromethane (10 mL),
and 70% metachloroperbenzoic acid (2.13 g) was added to the
solution, and then the mixture was stirred at room temperature for
16 hours. 1N sodium hydroxide was added and the precipitated
crystal was washed with 1N sodium hydroxide, water and methanol to
obtain the title compound (589 mg) as a colorless solid.
(b) Synthesis of
3-(3-chloro-4-hydroxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3--
benzothiazole
3-(3-chloro-4-methoxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3--
benzothiazole (586 mg) was dissolved in N,N-dimethylformamide (4
mL), and lithium chloride (241 mg) was added to the solution, and
then the mixture was stirred at 120.degree. C. for 2 hours. To the
reaction solution, 1N hydrochloric acid was added, and the
precipitated crystal was washed with water and then crystallized
from n-hexane-chloroform to obtain the title compound (310 mg) as a
colorless crystal.
1H-NMR.delta. (DMSO-d6): 3.34 (3H, s), 5.35 (2H, s), 7.44 (1H, dd,
J=7.6, 7.3 Hz), 7.76 (1H, dd, J=8.4, 7.3 Hz), 7.91 (1H, d, J=7.6
Hz), 7.99 (1H, d, J=2.2 Hz), 8.03 (1H, d, J=8.4 Hz), 8.09 (1H, d,
J=2.2 Hz). MS (m/z): 400 (M-H)-.
Example 23
3-(3-chloro-4-hydroxy-5-methylsulfinylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-b-
enzothiazole
3-(3-chloro-4-hydroxy-5-methylsulfanylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3--
benzothiazole (51 mg) was dissolved in tetrahydrofuran (0.5 mL) and
water (0.5 mL), and oxone (43 mg) was added to the solution, and
then the mixture was stirred at room temperature for 1 hour. To the
reaction solution, 1N hydrochloric acid was added, and then the
mixture was extracted with ethyl acetate. The organic layer was
washed with water and saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure and the obtained residue was crystallized from
n-hexane-diethylether to obtain the title compound (45 mg) as a
brown crystal.
1H-NMR.delta. (DMSO-d6): 2.82 (3H, s), 5.35 (2H, s), 7.43 (1H, dd,
J=7.6, 7.3 Hz), 7.75 (1H, dd, J=7.8, 7.6 Hz), 7.81 (1H, d, J=1.6
Hz), 7.86-8.02 (2H, m), 7.93 (1H, d, J=1.6 Hz). MS (m/z): 384
(M-H)-.
Example 24
3-(4-hydroxy-3-methylsulfonyl-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dihy-
dro-1,3-benzothiazole
(a) Synthesis of methyl 4-hydroxy-3-iodo-5-trifluoromethyl
benzoate
Methyl 4-hydroxy-3-trifluoromethyl benzoate (916 mg) was dissolved
in dichloromethane (15 mL), and N-iodosuccinimide (1.06 g) and
trifluoroacetic acid (5 mL) were added to the solution, and then
the mixture was stirred at room temperature for 1 hour. After the
solvent was distilled off under reduced pressure, 10% sodium
thiosulfate was added and the mixture was extracted with ethyl
acetate. The organic layer was washed with water and saturated
brine, and then dried over anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure to obtain the title
compound (1.44 g) as a brown solid.
(b) Synthesis of methyl
4-hydroxy-3-methylsulfanyl-5-trifluoromethyl benzoate
Methyl 4-hydroxy-3-iodo-5-trifluoromethyl benzoate (126 g) was
dissolved in N,N-dimethylformamide (12 mL), and 2,2'-bipyridine (57
mg), zinc powder (476 mg), nickel bromide (80 mg) and dimethyl
disulfide (172 mg) were added to the solution, and then the mixture
was stirred at 130.degree. C. for 1 hour. After the reaction
solution was filtered, 1N hydrochloric acid was added and the
reaction mixture was extracted with ethyl acetate. The organic
layer was washed with saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure and the obtained residue was purified by silica
gel column chromatography (n-hexane:ethyl acetate=4:1) to obtain
the title compound (276 mg) as a colorless crystal.
(c) Synthesis of methyl
4-methoxy-3-methylsulfanyl-5-trifluoromethyl benzoate
Methyl 4-hydroxy-3-methylsulfanyl-5-trifluoromethyl benzoate (327
mg) was dissolved in N,N-dimethylformamide (6 mL), and potassium
carbonate (1.70 g) and dimethylsulfuric acid (0.35 mL) were added
to the solution, and then the mixture was stirred at room
temperature for 1 hour. After the reaction solution was filtered,
1N hydrochloric acid was added and the reaction mixture was
extracted with ethyl acetate. The organic layer was washed with
saturated brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure to obtain the
title compound (344 mg) as a colorless oily substance.
(d) Synthesis of
4-methoxy-3-methylsulfanyl-5-trifluoromethylbenzoic acid
Methyl 4-methoxy-3-methylsulfanyl-5-trifluoromethyl benzoate (303
mg) was dissolved in tetrahydrofuran (3 mL) and water (1.5 mL), and
lithium hydroxide monohydrate (215 mg) was added to the solution,
and then the mixture was stirred at room temperature for 1 hour.
After the organic solvent was distilled off, the aqueous layer was
acidified with 1N hydrochloric acid and extracted with ethyl
acetate. The organic layer was washed with saturated brine, dried
over anhydrous sodium sulfate and then concentrated under reduced
pressure to obtain the title compound (277 mg) as a colorless
crystal.
1H-NMR.delta. (DMSO-d6): 2.56 (3H, s), 3.89 (3H, s), 7.90 (1H, d,
J=1.7 Hz), 8.00 (1H, d, J=1.7 Hz), 13.49 (1H, brs). MS (m/z): 265
(M-H)-.
(e) Synthesis of
4-methoxy-3-methylsulfanyl-5-trifluoromethylbenzoyl chloride
To 4-methoxy-3-methylsulfanyl-5-trifluoromethylbenzoic acid (277
mg), toluene (7 mL), N,N-dimethylformamide (1 droplet) and thionyl
chloride (0.12 mL) were added, and then the mixture was stirred at
60.degree. C. for 16 hours. The solvent was distilled off under
reduced pressure and the obtained residue was azeotroped with
toluene and used for the synthesis of (f).
(f) Synthesis of
3-(4-methoxy-3-methylsulfanyl-5-trifluoromethylbenzoyl)-2,3-dihydro-1,3-b-
enzothiazole
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol
(346 mg) and 37% formalin (0.23 mL) in the same manner as in
Example 1 was dissolved in chloroform (4 mL), and triethylamine
(0.43 mL) and 4-methoxy-3-methylsulfanyl-5-trifluoromethylbenzoyl
chloride were added to the solution, and then the mixture was
stirred at room temperature for 1 hour. After the solvent was
distilled off under reduced pressure, water was added and the
mixture was extracted with ethyl acetate. The organic layer was
washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated
brine, and then dried over anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure and the obtained residue
was used for the synthesis of (g).
(g) Synthesis of
3-(4-methoxy-3-methylsulfonyl-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dih-
ydro-1,3-benzothiazole
3-(4-methoxy-3-methylsulfanyl-5-trifluoromethylbenzoyl)-2,3-dihydro-1,3-b-
enzothiazole synthesized in (f) was dissolved in chloroform (8 mL),
and 70% metachloroperbenzoic acid (1.34 g) was added to the
solution, and then the mixture was stirred at room temperature for
20 hours and quenched with 10% sodium thiosulfate. After the
solvent was distilled off under reduced pressure, 1N sodium
hydroxide was added and the mixture was extracted with ethyl
acetate. The organic layer was washed with 1N sodium hydroxide and
saturated brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure and the obtained
residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=2:1) to obtain the title compound (310 mg)
as a colorless crystal.
(h) Synthesis of
3-(4-hydroxy-3-methylsulfonyl-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dih-
ydro-1,3-benzothiazole
3-(4-methoxy-3-methylsulfonyl-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dih-
ydro-1,3-benzothiazole (305 mg) was dissolved in
N,N-dimethylformamide (3 mL), and lithium chloride (288 mg) was
added to the solution, and then the mixture was stirred at
70.degree. C. for 1 hour. To the reaction solution, 1N hydrochloric
acid was added, and then the mixture was extracted with ethyl
acetate. The organic layer was washed with water, 1N hydrochloric
acid and saturated brine, and then dried over anhydrous sodium
sulfate. The solvent was distilled off under reduced pressure to
obtain the title compound (288 mg) as a colorless crystal.
1H-NMR.delta. (DMSO-d6): 5.34 (2H, s), 5.71 (3H, brs), 7.43 (1H,
dd, J=7.6, 7.6 Hz), 7.75 (1H, dd, J=8.4, 7.6 Hz), 7.90 (1H, d,
J=7.6 Hz), 8.02 (1H, d, J=8.4 Hz), 8.14 (1H, d, J=1.9 Hz), 825 (1H,
d, J=1.9 Hz). MS (m/z): 434 (M-H)-.
Example 25
3-(5-t-butyl-4-hydroxy-3-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3--
benzothiazole
(a) Synthesis of methyl
3-t-butyl-4-hydroxy-5-methylsulfanylbenzoate
Methyl 3-t-butyl-4-hydroxy-5-iodobenzoate (1.00 g) was dissolved in
N,N-dimethylformamide (10 mL), and 2,2'-bipyridine (47 mg), zinc
powder (391 mg), nickel bromide (66 mg) and dimethyl disulfide (142
mg) were added to the solution, and then the mixture was stirred at
130.degree. C. for 1 hour. After the reaction solution was
filtered, 1N hydrochloric acid was added and the reaction mixture
was extracted with ethyl acetate. The organic layer was washed with
saturated brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure and the obtained
residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=12:1) to obtain the title compound (382 mg)
as a pale yellow oily substance.
(b) Synthesis of methyl
3-t-butyl-4-methoxy-5-methylsulfanylbenzoate
Methyl 3-t-butyl-4-hydroxy-5-methylsulfanylbenzoate (377 mg) was
dissolved in N,N-dimethylformamide (7 mL), and potassium carbonate
(818 mg) and dimethylsulfuric acid (0.32 mL) were added to the
solution, and then the mixture was stirred at room temperature for
20 hours. Water was added to the reaction solution, and then the
reaction mixture was extracted with ethyl acetate. The organic
layer was washed with saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure to obtain the title compound (344 mg) as a pale
yellow oily substance.
(c) Synthesis of methyl 3-t-butyl-4-methoxy-5-methylsulfonyl
benzoate
Methyl 3-t-butyl-4-methoxy-5-methylsulfanylbenzoate (344 mg) was
dissolved in chloroform (7 mL), and 70% metachloroperbenzoic acid
(884 mg) was added to the solution, and then the mixture was
stirred at room temperature for 3 hours. After the solvent was
distilled off under reduced pressure, 1N sodium hydroxide was added
and the mixture was extracted with ethyl acetate. The organic layer
was washed with 1N sodium hydroxide and saturated brine, and then
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure to obtain the title compound (387 mg) as a
colorless crystal.
(d) Synthesis of 3-t-butyl-4-methoxy-5-methylsulfonyl benzoic
acid
Methyl 3-t-butyl-4-methoxy-5-methylsulfonyl benzoate (382 mg) was
dissolved in tetrahydrofuran (4 mL) and water (2 mL), and lithium
hydroxide monohydrate (320 mg) was added to the solution, and then
the mixture was stirred at room temperature for 5 hours. After the
organic solvent was distilled off, the aqueous layer was acidified
with 1N hydrochloric acid and then extracted with ethyl acetate.
The organic layer was washed with saturated brine, dried over
anhydrous sodium sulfate and then concentrated under reduced
pressure to obtain the title compound (372 mg) as a colorless
crystal.
1H-NMR.delta. (CDCl.sub.3): 1.43 (9H, s), 3.32 (3H, s), 3.99 (3H,
s), 8.26 (1H, d, J=2.2 Hz), 8.32 (1H, d, J=22 Hz). MS (m/z): 285
(M-H)-.
(e) Synthesis of 3-t-butyl-4-methoxy-5-methylsulfonylbenzoyl
chloride
To 3-t-butyl-4-methoxy-5-methylsulfonyl benzoic acid (200 mg),
toluene (4 mL), N,N-dimethylformamide (1 droplet) and thionyl
chloride (80 .mu.L) were added to the solution, and then the
mixture was stirred at 60.degree. C. for 16 hours. The solvent was
distilled off under reduced pressure and the obtained residue was
azeotroped with toluene and used for the synthesis of (f).
(f) Synthesis of
3-(3-t-butyl-4-methoxy-5-methylsulfonylbenzoyl)-2,3-dihydro-1,3-benzothia-
zole
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol
(182 mg) and 37% formalin (87 .mu.L) in the same manner as in
Example 1 was dissolved in chloroform (4 mL), and triethylamine
(0.29 mL) and 3-t-butyl-4-methoxy-5-methanesulfonylbenzoyl chloride
were added to the solution, and then the mixture was stirred at
room temperature for 1 hour. The solvent was distilled off under
reduced pressure, water was added and then the mixture was
extracted with ethyl acetate. The organic layer was washed with 1N
hydrochloric acid, 1N sodium hydroxide and saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure and the obtained residue was purified by
silica gel column chromatography (n-hexane:ethyl acetate=4:1) to
obtain the title compound (246 mg) as a pale yellow amorphous
product.
(g) Synthesis of
3-(3-t-butyl-4-methoxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-
-benzothiazole
3-(3-t-butyl-4-methoxy-5-methylsulfonylbenzoyl)-2,3-dihydro-1,3-benzothia-
zole (241 mg) was dissolved in chloroform (5 mL), and 70%
metachloroperbenzoic acid (410 mg) was added to the solution, and
then the mixture was stirred at room temperature for 16 hours and
quenched with 10% sodium thiosulfate. After the solvent was
distilled off under reduced pressure, 1N sodium hydroxide was added
and the mixture was extracted with ethyl acetate. The organic layer
was washed with 1N sodium hydroxide and saturated brine, and then
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure to obtain the title compound (236 mg) as a
colorless amorphous product.
(h) Synthesis of
3-(3-t-butyl-4-hydroxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-
-benzothiazole
3-(3-t-butyl-4-methoxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-
-benzothiazole (232 mg) was dissolved in N,N-dimethylformamide (5
mL), and lithium chloride (225 mg) was added to the solution, and
then the mixture was stirred at 130.degree. C. for 2 hours. To the
reaction solution, 1N hydrochloric acid was added, and then the
mixture was extracted with ethyl acetate. The organic layer was
washed with water, 1N hydrochloric acid and saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure and the obtained residue was purified by
silica gel column chromatography (n-hexane:ethyl acetate=1:1) to
obtain the title compound (201 mg) as a colorless amorphous
product.
1H-NMR.delta. (DMSO-d6): 1.40 (9H, s), 3.42 (3H, s), 5.33 (2H, s),
7.43 (1H, dd, J=7.6, 7.6 Hz), 7.75 (1H, ddd, J=8.3, 7.6, 1.3 Hz),
7.80 (1H, d, J=2.2 Hz), 7.91 (1H, d, J=7.6 Hz), 7.97 (1H, d, J=8.3
Hz), 7.99 (1H, d, J=2.2 Hz), 10.06 (1H, brs). MS (m/z): 422
(M-H)-.
Example 26
3-(4-hydroxy-3-methoxy-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-
-benzothiazole
(a) Synthesis of ethyl 4-benzyloxy-3-methoxy-5-trifluoromethyl
benzoate
Ethyl 4-hydroxy-3-methoxy-5-trifluoromethyl benzoate (583 mg) was
dissolved in N,N-dimethylformamide (5 mL), and 60% sodium hydride
(132 mg) was added to the solution at 0.degree. C. After stirring
the mixture for 30 minutes, benzyl bromide (0.31 mL) was added to
the solution and then the mixture was stirred for 14 hours. Water
was added to the reaction solution, and then the reaction mixture
was extracted with ethyl acetate. The organic layer was washed with
water and saturated brine, and then dried over anhydrous sodium
sulfate. The solvent was distilled off under reduced pressure and
the obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=7:1) to obtain the title
compound (704 mg) as a yellow oily substance.
(b) Synthesis of 4-benzyloxy-3-methoxy-5-trifluoromethylbenzoic
acid
Ethyl 4-benzyloxy-3-methoxy-5-trifluoromethylbenzoate (704 mg) was
dissolved in tetrahydrofuran (6 mL) and water (2 mL), and lithium
hydroxide monohydrate (333 mg) was added to the solution, and then
the mixture was stirred at 60.degree. C. for 3 hours. After the
organic solvent was distilled off, the mixture was acidified with
1N hydrochloric acid and then extracted with ethyl acetate. The
organic layer was washed with saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure to obtain the title compound (606 mg) as a
colorless crystal.
1H-NMR.delta. (CDCl3): 4.00 (3H, s), 5.21 (2H, s), 7.33-7.54 (5H,
m), 7.85 (1H, s), 8.00 (1H, s). MS (m/z): 325 (M-H)-.
(c) Synthesis of 4-benzyloxy-3-methoxy-5-trifluoromethylbenzoyl
chloride
To 4-benzyloxy-3-methoxy-5-trifluoromethylbenzoic acid (601 mg),
toluene (6 mL), N,N-dimethylformamide (1 droplet) and thionyl
chloride (0.16 mL) were added, and then the mixture was stirred at
60.degree. C. for 16 hours. The solvent was distilled off under
reduced pressure and then azeotroped with toluene to obtain the
title compound (657 mg) as a yellow oily substance.
(d) Synthesis of
3-(4-benzyloxy-3-methoxy-5-trifluoromethylbenzoyl)-2,3-dihydro-1,3-benzot-
hiazole
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol
(346 mg) and 37% formalin (0.23 mL) in the same manner as in
Example 1 was dissolved in dichloromethane (3 mL), and
diisopropylethylamine (0.63 mL) and
4-benzyloxy-3-methoxy-5-trifluoromethylbenzoyl chloride (657 mg)
were added to the solution, and then the mixture was stirred at
room temperature for 1 hour. The solvent was distilled off under
reduced pressure and water was added, and then the mixture was
extracted with ethyl acetate. The organic layer was washed with 1N
hydrochloric acid, 1N sodium hydroxide and saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure and the obtained residue was purified by
silica gel column chromatography (n-hexane:ethyl acetate=6:1) to
obtain the title compound (578 mg) as a yellow oily substance.
(e) Synthesis of
3-(4-benzyloxy-3-methoxy-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dihydro--
1,3-benzothiazole
3-(4-benzyloxy-3-methoxy-5-trifluoromethylbenzoyl)-2,3-dihydro-1,3-benzot-
hiazole (578 mg) was dissolved in dichloromethane (10 mL), and 70%
metachloroperbenzoic acid (1.94 g) was added to the solution. After
stirring the mixture at room temperature for 4 hours, 1N sodium
hydroxide was added and then the mixture was extracted with ethyl
acetate. The organic layer was washed with 1N sodium hydroxide and
saturated brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure to obtain the
title compound (574 mg) as a colorless oily substance.
(f) Synthesis of
3-(4-hydroxy-3-methoxy-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dihydro-1,-
3-benzothiazole
3-(4-benzyloxy-3-methoxy-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dihydro--
1,3-benzothiazole (574 mg) was dissolved in tetrahydrofuran (6 mL),
and 5% palladium-carbon (310 mg) was added to the solution, and
then the mixture was stirred at room temperature for 22 hours under
a hydrogen atmosphere. The reaction solution was filtered, and then
the solvent was distilled off under reduced pressure and the
obtained residue was crystallized from n-hexane-chloroform to
obtain the title compound (353 mg) as a colorless crystal.
1H-NMR.delta. (DMSO-d6): 3.93 (3H, s), 5.35 (2H, s), 7.43 (1H, dd,
J=8.1, 7.3 Hz), 7.47 (1H, s), 7.54 (1H, s), 7.76 (1H, dd, J=7.3,
7.3 Hz), 7.90 (1H, d, J=7.3 Hz), 8.02 (1H, d, J=8.1 Hz), 10.68 (1H,
s). MS (m/z): 386 (M-H)-.
Example 27
3-(3-dimethylcarbamoyl-4-hydroxy-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3-d-
ihydro-1,3-benzothiazole
(a) Synthesis of methyl 3-formyl-4-methoxy-5-trifluoromethyl
benzoate
3-formyl-4-methoxy-5-trifluoromethylbenzoic acid (5.00 g) was
dissolved in methanol (30 mL), and
1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (4.25
g) was added to the solution, and then the mixture was stirred at
mom temperature for 90 minutes. The solvent was distilled off under
reduced pressure and water was added, and then the mixture was
extracted with ethyl acetate. The organic layer was washed with 1N
sodium hydroxide and saturated brine, and then dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure and the obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=4:1) to obtain the title
compound (2.98 g) as a colorless crystal.
(b) Synthesis of 4-methoxy-5-trifluoromethylisophthalic
acid-1-methyl ester
Methyl 3-formyl-4-methoxy-5-trifluoromethyl benzoate (1.50 g) was
dissolved in acetonitrile (15 mL) and an aqueous 5% citric acid
solution, and 2-methyl-2-butene (2.00 g) and sodium chlorite (776
mg) were added to the solution, and then the mixture was stirred at
room temperature for 1 hour. The solvent was distilled off under
reduced pressure and 1N hydrochloric acid was added, and then the
mixture was extracted with ethyl acetate. The organic layer was
washed with 10% sodium thiosulfate and saturated brine, and then
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure and the obtained crystal was washed with
n-hexane to obtain the title compound (1.15 g) as a colorless
crystal.
(c) Synthesis of methyl
3-dimethylcarbamoyl-4-methoxy-5-trifluoromethyl benzoate
4-methoxy-5-trifluoromethylisophthalic acid-1-methyl ester (500 mg)
was dissolved in dichloromethane (10 mL), and dimethylamine
hydrochloride (440 mg), 1-ethyl-3-(3-dimethylaminopropyl)
carbodiimide hydrochloride (1.56 g) and triethylamine (3.00 mL) was
added to the solution, and then the mixture was stirred at room
temperature for 4 hours. The solvent was distilled off under
reduced pressure and 1N hydrochloric acid was added, and then the
mixture was extracted with ethyl acetate. The organic layer was
washed with 1N sodium hydroxide and saturated brine, and then dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure to obtain the title compound (356 mg) as a pale
yellow crystal.
(d) Synthesis of
3-dimethylcarbamoyl-4-methoxy-5-trifluoromethylbenzoic acid
Methyl 3-dimethylcarbamoyl-4-methoxy-5-trifluoromethyl benzoate
(348 mg) was dissolved in tetrahydrofuran (3 mL) and water (1.5
mL), and lithium hydroxide monohydrate (191 mg) was added to the
solution, and then the mixture was stirred at room temperature for
1 hour. The organic solvent was distilled off under reduced
pressure and acidified with 1N hydrochloric acid, and then the
mixture was extracted with ethyl acetate. The organic layer was
washed with saturated brine, and then dried over anhydrous sodium
sulfate. The solvent was distilled off under reduced pressure to
obtain the title compound (341 mg) as a colorless crystal.
1H-NMR.delta. (CDCl3): 2.91 (3H, s), 3.18 (3H, s), 3.96 (3H, s),
8.22 (1H, d, J=2.3 Hz), 8.35 (1H, dd, J=2.3, 0.6 Hz). MS (m/z): 290
(M-H)-.
(e) Synthesis of
3-dimethylcarbamoyl-4-methoxy-5-trifluoromethylbenzoyl chloride
To 3-dimethylcarbamoyl-4-methoxy-5-trifluoromethylbenzoic acid (333
mg), toluene (3 mL), N,N-dimethylformamide (1 droplet) and thionyl
chloride (0.13 mL) was added, and then the mixture was stirred at
60.degree. C. for 6 hours. The solvent was distilled off under
reduced pressure and the obtained residue was azeotroped with
toluene and used for the synthesis of (f).
(f) Synthesis of
3-(3-dimethylcarbamoyl-4-methoxy-5-trifluoromethylbenzoyl)-2,3-dihydro-1,-
3-benzothiazole
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol
(214 mg) and 37% formalin (0.14 mL) in the same manner as in
Example 1 was dissolved in chloroform (4 mL), and triethylamine
(0.47 mL) and
3-dimethylcarbamoyl-4-methoxy-5-trifluoromethylbenzoyl chloride
were added to the solution, and then the mixture was stirred at
room temperature for 1 hour. The solvent was distilled off under
reduced pressure and water was added, and then the mixture was
extracted with ethyl acetate. The organic layer was washed with 1N
hydrochloric acid, 1N sodium hydroxide and saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure and the obtained residue was used for
the synthesis of (g).
(g) Synthesis of
3-(3-dimethylcarbamoyl-4-methoxy-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3--
dihydro-1,3-benzothiazole
3-(3-dimethylcarbamoyl-4-methoxy-5-trifluoromethylbenzoyl)-2,3-dihydro-1,-
3-benzothiazole was dissolved in chloroform (8 mL), and 70%
metachloroperbenzoic acid (718 mg) was added to the solution, and
then the mixture was stirred at room temperature for 20 hours and
quenched with 10% sodium thiosulfate. The solvent was distilled off
under reduced pressure and 1N sodium hydroxide was added, and then
the mixture was extracted with ethyl acetate. The organic layer was
washed with 1N sodium hydroxide and saturated brine, and then dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure and the obtained residue was purified by silica
gel column chromatography (n-hexane:ethyl acetate=2:1) to obtain
the title compound (298 mg) as a pale yellow amorphous product.
(h) Synthesis of
3-(3-dimethylcarbamoyl-4-hydroxy-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3--
dihydro-1,3-benzothiazole
3-(3-dimethylcarbamoyl-4-methoxy-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3--
dihydro-1,3-benzothiazole (291 mg) was dissolved in
N,N-dimethylformamide (3 mL), and lithium chloride (279 mg) was
added to the solution, and then the mixture was stirred at
120.degree. C. for 2 hours. To the reaction solution, 1N
hydrochloric acid was added, and then the mixture was extracted
with ethyl acetate. The organic layer was washed with 1N
hydrochloric acid and saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure to obtain the title compound (257 mg) as a
colorless crystal.
1H-NMR.delta. (DMSO-d6): 2.96 (6H, s), 5.39 (2H, s), 7.43 (1H, dd,
J=7.6, 7.6 Hz), 7.55 (1H, ddd, J=8.4, 7.6, 1.3 Hz), 7.79 (1H, d,
J=2.1 Hz), 7.90 (1H, d, J=7.6 Hz), 7.93 (1H, d, J=2.1 Hz), 8.02
(1H, d, J=8.4 Hz), 11.27 (1H, s). MS (m/z): 427 (M-H)-.
Example 28
3-(4-hydroxy-3-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothia-
zole
(a) Synthesis of acetic acid-2-trifluoromethylphenyl ester
2-trifluoromethylphenol (20.00 g) was dissolved in chloroform (160
mL), and triethylamine (34.0 mL) and acetic anhydride (12.4 mL)
were added to the solution, and then the mixture was stirred at
room temperature for 3 hours. The solvent was distilled off under
reduced pressure and water was added, and then the mixture was
extracted with ethyl acetate. The organic layer was washed with
saturated brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure to obtain the
title compound (23.76 g) as a pale yellow oily substance.
(b) Synthesis of 1-(4-hydroxy-3-trifluoromethylphenyl)ethanone
Acetic acid-2-trifluoromethylphenyl ester (10.00 g) was dissolved
in trifluoromethanesulfonic acid (10.0 mL), and the solution was
stirred at room temperature for 16 hours. The reaction solution was
poured into ice water, and the reaction mixture was extracted with
ethyl acetate. The organic layer was washed with water and
saturated brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure and the obtained
crystal was washed with n-hexane to obtain the title compound (4.47
g) as a colorless crystal.
(c) Synthesis of
1-(4-methoxymethoxy-3-trifluoromethylphenyl)ethanone
1-(4-hydroxy-3-trifluoromethylphenyl)ethanone (2.01 g) was
dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate
(2.70 g) and chloromethyl methyl ether (1.10 mL) were added to the
solution, and then the mixture was stirred at room temperature for
1 hour. Water was added to the reaction solution and the reaction
mixture was extracted with ethyl acetate. The organic layer was
washed with water and saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure to obtain the title compound (2.33 g) as a pale
yellow oily substance.
(d) Synthesis of methyl 4-hydroxy-3-trifluoromethoxybenzoate
1-(4-methoxymethoxy-3-trifluoromethylphenyl)ethanone (2.33 g) was
dissolved in methanol (20 mL), and a 5M sodium methoxide-methanol
solution (9.40 mL) and N-bromosuccinimide (5.10 g) were added to
the solution, and then the mixture was stirred at room temperature
for 30 minutes. The solvent was distilled off under reduced
pressure and water was added, and then the mixture was extracted
with ethyl acetate. The organic layer was washed with 10% sodium
thiosulfate and saturated brine, and then dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure and 4N hydrochloric acid-ethyl acetate (20 mL) was added,
and then the mixture was stirred at room temperature for 30
minutes. The reaction solution was washed with water and saturated
brine, and then dried over anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure to obtain the title
compound (1.42 g) as a colorless crystal.
(e) Synthesis of methyl 4-benzyloxy-3-trifluoromethyl benzoate
Methyl 4-hydroxy-3-trifluoromethoxybenzoate (936 mg) was dissolved
in N,N-dimethylformamide (10 mL), and potassium carbonate (1.29 g)
and benzyl bromide (0.58 mL) were added to the solution, and then
the mixture was stirred at room temperature for 24 hours. Water was
added to the reaction solution and the reaction mixture was
extracted with ethyl acetate. The organic layer was washed with
water and saturated brine, and then dried over anhydrous sodium
sulfate. The solvent was distilled off under reduced pressure and
the obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=4:1) to obtain the title
compound (1.70 g) as a yellow crystal.
(f) Synthesis of 4-benzyloxy-3-trifluoromethylbenzoic acid
Methyl 4-benzyloxy-3-trifluoromethyl benzoate (1.38 g) was
dissolved in tetrahydrofuran (10 mL) and water (5 mL), and lithium
hydroxide monohydrate (1.49 g) was added to the solution, and then
the mixture was stirred at room temperature for 20 hours. The
solvent was distilled off under reduced pressure and 1N
hydrochloric acid was added, and then the mixture was extracted
with ethyl acetate. The organic layer was washed with saturated
brine, and then dried over anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure to obtain the title
compound (1.25 g) as a pale yellow crystal.
1H-NMR.delta. (DMSO-d6): 5.38 (2H, s), 7.31-7.51 (6H, m), 8.12 (1H,
d, J=2.1 Hz), 8.19 (1H, d, J=8.6, 2.1 Hz), 13.12 (1H, brs). MS
(m/z): 269 (M-H)-.
(g) Synthesis of 4-benzyloxy-3-trifluoromethylbenzoyl chloride
To 4-benzyloxy-3-trifluoromethylbenzoic acid (444 mg), toluene (5
mL), N,N-dimethylformamide (2 droplets) and thionyl chloride (0.16
mL) were added, and then the mixture was stirred at 60.degree. C.
for 20 hours. The solvent was distilled off under reduced pressure
and then azeotroped with toluene, and the obtained product was used
for the synthesis of (h).
(h) Synthesis of
3-(4-benzyloxy-3-trifluoromethylbenzoyl)-2,3-dihydro-1,3-benzothiazole
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol
(282 mg) and 37% formalin (0.19 mL) in the same manner as in
Example 1 was dissolved in chloroform (6 mL), and triethylamine
(0.62 mL) and 4-benzyloxy-3-trifluoromethylbenzoyl chloride were
added to the solution, and then the mixture was stirred at mom
temperature for 1.5 hours. The solvent was distilled off under
reduced pressure and water was added, and then the mixture was
extracted with ethyl acetate. The organic layer was washed with 1N
hydrochloric acid, 1N sodium hydroxide and saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure and the obtained residue was purified by
silica gel column chromatography (n-hexane:ethyl acetate=4:1) to
obtain the title compound (356 mg) as a pale yellow oily
substance.
(i) Synthesis of
3-(4-benzyloxy-3-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzot-
hiazole
3-(4-benzyloxy-3-trifluoromethylbenzoyl)-2,3-dihydro-1,3-benzothiazole
(600 mg) was dissolved in chloroform (10 mL), and 70%
metachloroperbenzoic acid (1.04 g) was added to the solution, and
then the mixture was stirred at room temperature for 20 hours and
quenched with 10% sodium thiosulfate. The solvent was distilled off
under reduced pressure and 1N sodium hydroxide was added, and then
the mixture was extracted with ethyl acetate. The organic layer was
washed with 1N sodium hydroxide and saturated brine, and then dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure and the obtained residue was purified by silica
gel column chromatography (n-hexane:ethyl acetate=2:1) to obtain
the title compound (495 mg) as a colorless crystal.
(j) Synthesis of
3-(4-hydroxy-3-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothi-
azole
3-(4-benzyloxy-3-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzot-
hiazole (490 mg) was dissolved in tetrahydrofuran (5 mL) and
methanol (5 mL), and 20% palladium hydroxide-carbon (100 mg) was
added to the solution, and then the mixture was stirred at room
temperature for 6 hours under a hydrogen atmosphere. After the
reaction solution was filtered, the solvent was distilled off under
reduced pressure and then the obtained residue was crystallized
from diethylether to obtain the title compound (397 mg) as a
colorless crystal.
1H-NMR.delta. (DMSO-d6): 5.29 (2H, s), 7.14 (1H, d, J=8.4 Hz), 7.41
(1H, ddd, J=8.2, 7.8, 0.9 Hz), 7.72 (1H, ddd, J=8.5, 7.3, 1.3 Hz),
7.80 (1H, dd, J=8.4, 2.2 Hz), 7.84-7.88 (2H, m), 7.91 (1H, d, J=8.2
Hz), 11.35 (1H, brs). MS (m/z): 356 (M-H)-.
Example 29
3-(3-chloro-4-hydroxy-5-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothi-
azole
(a) Synthesis of 4-benzyloxy-3-chloro-5-methoxybenzoyl chloride
To 4-benzyloxy-3-chloro-5-methoxybenzoic acid (541 mg), toluene
(5.4 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride
(0.16 mL) were added, and then the mixture was stirred at
60.degree. C. for 16 hours. The solvent was distilled off under
reduced pressure and then azeotroped with toluene to obtain the
title compound (578 mg) as a yellow solid.
(b) Synthesis of
3-(4-benzyloxy-3-chloro-5-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol
(347 mg) and 37% formalin (0.23 mL) in the same manner as in
Example 1 was dissolved in dichloromethane (3 mL), and
diisopropylethylamine (0.63 mL) and
4-benzyloxy-3-chloro-5-methoxybenzoyl chloride (578 mg) were added
to the solution, and then the mixture was stirred at room
temperature for 1.5 hours. The solvent was distilled off under
reduced pressure and water was added, and then the mixture was
extracted with ethyl acetate. The organic layer was washed with 1N
hydrochloric acid, 1N sodium hydroxide and saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure and the obtained residue was purified by
silica gel column chromatography (n-hexane:ethyl acetate=6:1) to
obtain the title compound (498 mg) as a pale yellow oily
substance.
(c) Synthesis of
3-(4-benzyloxy-3-chloro-5-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzo-
thiazole
3-(4-benzyloxy-3-chloro-5-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole
(498 mg) was dissolved in dichloromethane (10 mL), and 70%
metachloroperbenzoic acid (1.22 g) was added to the solution. After
stirring the mixture at room temperature for 16 hours, 1N sodium
hydroxide was added, and then the mixture was extracted with ethyl
acetate. The organic layer was washed with 1N sodium hydroxide and
saturated brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure to obtain the
title compound (521 mg) as a pale yellow oily substance.
(d) Synthesis of
3-(3-chloro-4-hydroxy-5-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzoth-
iazole
3-(4-benzyloxy-3-chloro-5-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzo-
thiazole (519 mg) was dissolved in tetrahydrofuran (5 mL), and 20%
palladium hydroxide-carbon (101 mg) was added to the solution, and
then the mixture was stirred at room temperature for 21 hours under
a hydrogen atmosphere. After the reaction solution was filtered,
the solvent was distilled off under reduced pressure and then the
obtained residue was crystallized from chloroform to obtain the
title compound (185 mg) as a colorless crystal.
1H-NMR.delta. (DMSO-d6): 3.88 (3H, s), 5.34 (2H, s), 7.27 (1H, s),
7.35 (1H, s), 7.43 (1H, dd, J=7.6 Hz, 7.6 Hz), 7.75 (1H, dd, J=8.4,
7.6 Hz), 7.90 (1H, d, J=7.6 Hz), 7.99 (1H, d, J=8.4 Hz). MS (m/z):
352 (M-H)-.
Example 30
3-[4-hydroxy-3-(pyrrolidine-1-carbonyl)-5-trifluoromethylbenzoyl]-1,1-diox-
o-2,3-dihydro-1,3-benzothiazole
(a) Synthesis of methyl
4-methoxy-3-(pyrrolidine-1-carbonyl)-5-trifluoromethyl benzoate
4-methoxy-5-trifluoromethylisophthalic acid-1-methyl ester (4.35 g)
was dissolved in dichloromethane (50 mL), and pyrrolidine (1.10 g)
and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride
(2.99 g) were added to the solution, and then the mixture was
stirred at room temperature for 16 hours. The solvent was distilled
off under reduced pressure and 1N hydrochloric acid was added, and
then the mixture was extracted with ethyl acetate. The organic
layer was washed with 1N sodium hydroxide and saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure and the obtained residue was purified by
silica gel column chromatography (n-hexane:ethyl acetate=2:3) to
obtain the title compound (1.33 g) as a brown oily substance.
(b) Synthesis of
4-methoxy-3-(pyrrolidine-1-carbonyl)-5-trifluoromethylbenzoic
acid
Methyl 4-methoxy-3-(pyrrolidine-1-carbonyl)-5-trifluoromethyl
benzoate (1.33 g) was dissolved in tetrahydrofuran (8 mL) and water
(4 mL), and lithium hydroxide monohydrate (708 mg) was added to the
solution, and then the mixture was stirred at room temperature for
1 hour. The organic solvent was distilled off under reduced
pressure and the aqueous layer was washed with diisopropylether.
The aqueous layer was acidified with 1N hydrochloric acid and then
extracted with ethyl acetate. The organic layer was washed with
saturated brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure to obtain the
title compound (790 mg) as a colorless amorphous product.
(c) Synthesis of
4-methoxy-3-(pyrrolidine-1-carbonyl)-5-trifluoromethylbenzoyl
chloride
To 4-methoxy-3-(pyrrolidine-1-carbonyl)-5-trifluoromethylbenzoic
acid (785 mg), toluene (8 mL) and oxalyl chloride (0.64 mL) were
added, and then the mixture was stirred at room temperature for 22
hours. The solvent was distilled off under reduced pressure and the
obtained product was used for the synthesis of (d).
(d) Synthesis of
3-[4-methoxy-3-(pyrrolidine-1-carbonyl)-5-trifluoromethylbenzoyl]-2,3-dih-
ydro-1,3-benzothiazole
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol
(464 mg) and 37% formalin (0.31 mL) in the same manner as in
Example 1 was dissolved in chloroform (10 mL), and triethylamine
(1.03 mL) and
4-methoxy-3-(pyrrolidine-1-carbonyl)-5-trifluoromethylbenzoyl
chloride were added to the solution, and then the mixture was
stirred at room temperature for 2 hours. The solvent was distilled
off under reduced pressure and water was added, and then the
mixture was extracted with ethyl acetate. The organic layer was
washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated
brine, and then dried over anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure and the obtained residue
was purified by silica gel column chromatography (n-hexane:ethyl
acetate=1:2) to obtain the title compound (778 mg) as a pale yellow
amorphous product.
(e) Synthesis of
3-[4-methoxy-3-(pyrrolidine-1-carbonyl)-5-trifluoromethylbenzoyl]-1,1-dio-
xo-2,3-dihydro-1,3-benzothiazole
3-[4-methoxy-3-(pyrrolidine-1-carbonyl)-5-trifluoromethylbenzoyl]-2,3-dih-
ydro-1,3-benzothiazole (773 mg) was dissolved in chloroform (15
mL), and 70% metachloroperbenzoic acid (1.22 g) was added to the
solution, and then the mixture was stirred at room temperature for
16 hours and quenched with 10% sodium thiosulfate. After the
solvent was distilled off under reduced pressure, 1N sodium
hydroxide was added, and then the mixture was extracted with ethyl
acetate. The organic layer was washed with 1N sodium hydroxide and
saturated brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure to obtain the
title compound (720 mg) as a white amorphous product.
(f) Synthesis of
3-[4-hydroxy-3-(pyrrolidine-1-carbonyl)-5-trifluoromethylbenzoyl]-1,1-dio-
xo-2,3-dihydro-1,3-benzothiazole
3-[4-methoxy-3-(pyrrolidine-1-carbonyl)-5-trifluoromethylbenzoyl]-1,1-dio-
xo-2,3-dihydro-1,3-benzothiazole (715 mg) was dissolved in
N,N-dimethylformamide (7 mL), and lithium chloride (649 mg) was
added to the solution, and then the mixture was stirred at
120.degree. C. for 2 hours. To the reaction solution, 1N
hydrochloric acid was added, and then the mixture was extracted
with ethyl acetate. The organic layer was washed with 1N
hydrochloric acid and saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure to obtain the title compound (654 mg) as a
colorless amorphous product.
1H-NMR.delta. (DMSO-d6): 1.86 (4H, br), 3.45-3.60 (4H, t, J=6.5
Hz), 5.37 (2H, s), 7.43 (1H, ddd, J=7.8, 7.8, 0.8 Hz), 7.76 (1H,
ddd, J=8.4, 7.8, 1.3 Hz), 7.90 (2H, br), 8.03 (1H, d, J=8.4 Hz),
12.29 (1H, s). MS (m/z): 453 (M-H)-.
Example 31
3-[4-hydroxy-3-(1,3-thiazolidine-3-carbonyl)-5-trifluoromethylbenzoyl]-1,1-
-dioxo-2,3-dihydro-1,3-benzothiazole
(a) Synthesis of 3-formyl-4-methoxy-5-trifluoromethylbenzoyl
chloride
To 3-formyl-4-methoxy-5-trifluoromethylbenzoic acid (2.05 g),
toluene (20 mL), N,N-dimethylformamide (2 droplets) and thionyl
chloride (0.70 mL) were added, and then the mixture was stirred at
60.degree. C. for 6.5 hours. The solvent was distilled off under
reduced pressure and then azeotroped with toluene to obtain the
title compound (2.42 g) as a brown oily substance.
(b) Synthesis of
3-(3-formyl-4-methoxy-5-trifluoromethylbenzoyl)-2,3-dihydro-1,3-benzothia-
zole
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol
(1.55 g) and 37% formalin (1.0 mL) in the same manner as in Example
1 was dissolved in dichloromethane (15 mL), and
diisopropylethylamine (2.7 mL) and
3-formyl-4-methoxy-5-trifluoromethylbenzoyl chloride (2.42 g) were
added to the solution, and then the mixture was stirred at room
temperature for 14 hours. The solvent was distilled off under
reduced pressure and water was added, and then the mixture was
extracted with ethyl acetate. The organic layer was washed with 1N
hydrochloric acid, 1N sodium hydroxide and saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure and the obtained residue was purified by
silica gel column chromatography (n-hexane:ethyl acetate=5:1) to
obtain the title compound (1.44 g) as a yellow oily substance.
(c) Synthesis of
3-(3-diethoxymethyl-4-methoxy-5-trifluoromethylbenzoyl)-2,3-dihydro-1,3-b-
enzothiazole
3-(3-formyl-4-methoxy-5-trifluoromethylbenzoyl)-2,3-dihydro-1,3-benzothia-
zole (277 mg) was dissolved in ethanol (1.5 mL) and triethyl
orthoformate (0.16 mL), Amberlyst-15 (27 mg) was added to the
solution, and then the mixture was refluxed for 3.5 hours. The
reaction solution was filtered, and then the solvent was distilled
off under reduced pressure to obtain the title compound (326 mg) as
a yellow oily substance.
(d) Synthesis of
3-(3-formyl-4-methoxy-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-
-benzothiazole
3-(3-formyl-4-methoxy-5-trifluoromethylbenzoyl)-2,3-dihydro-1,3-benzothia-
zole (326 mg) was dissolved in dichloromethane (6 mL), and 70%
metachloroperbenzoic acid (754 mg) was added to the solution: After
stirring the mixture at mom temperature for 2 hours, 1N sodium
hydroxide was added and then the mixture was extracted with ethyl
acetate. The organic layer was washed with 1N sodium hydroxide and
saturated brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure and the obtained
residue was dissolved in ethyl acetate (3 mL), and 4N hydrochloric
acid-ethyl acetate (0.74 mL) was added to the solution, and then
the mixture was stirred at room temperature for 2 hours. The
reaction solution was washed with water and saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure to obtain the title compound (248 mg) as
a pale yellow oily substance.
(e) Synthesis of
5-(1,1-dioxo-2,3-dihydro-1,3-benzothiazole-3-carbonyl)-2-methoxy-3-triflu-
oromethylbenzoic acid
3-(3-formyl-4-methoxy-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-
-benzothiazole (248 mg) was dissolved in methanol (2.5 mL) and an
aqueous 10% citric acid solution (2.5 mL), and 2-methyl-2-butene
(0.33 mL) and sodium chlorite (84 mg) were added to the solution,
and then the mixture was stirred at room temperature for 1 hour.
The solvent was distilled off under reduced pressure and 1N
hydrochloric acid was added, and then the mixture was extracted
with ethyl acetate. The organic layer was washed with an aqueous
10% sodium thiosulfate solution and saturated brine, and then dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure to obtain the title compound (277 mg) as a pale
yellow oily substance.
(f) Synthesis of
3-[4-methoxy-3-(1,3-thiazolidine-3-carbonyl)-5-trifluoromethylbenzoyl]-1,-
1-dioxo-2,3-dihydro-1,3-benzothiazole
5-(1,1-dioxo-2,3-dihydro-1,3-benzothiazole-3-carbonyl)-2-methoxy-3-triflu-
oromethylbenzoic acid (277 mg) was dissolved in dichloromethane (3
mL), thiazolidine (0.10 mL) and 1-ethyl-3-(3-dimethylaminopropyl)
carbodiimide hydrochloride (238 mg) were added to the solution, and
then the mixture was stirred at room temperature for 19 hours. The
solvent was distilled off under reduced pressure and 1N
hydrochloric acid was added and then the mixture was extracted with
ethyl acetate. The organic layer was washed with 1N hydrochloric
acid, 1N sodium hydroxide and saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure and the obtained residue was purified by silica
gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain
the title compound (138 mg) as a colorless oily substance.
(g) Synthesis of
3-[4-hydroxy-3-(1,3-thiazolidine-3-carbonyl)-5-trifluoromethylbenzoyl]-1,-
1-dioxo-2,3-dihydro-1,3-benzothiazole
3-[4-methoxy-3-(1,3-thiazolidine-3-carbonyl)-5-trifluoromethylbenzoyl]-1,-
1-dioxo-2,3-dihydro-1,3-benzothiazole (138 mg) was dissolved in
N,N-dimethylformamide (2 mL), and lithium chloride (118 mg) was
added to the solution, and then the mixture was stirred at
120.degree. C. for 1.5 hours. To the reaction solution, 1N
hydrochloric acid was added, and then the mixture was extracted
with ethyl acetate. The organic layer was washed with water and
saturated brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure and the obtained
residue was crystallized from n-hexane-chloroform to obtain the
title compound (47 mg) as a pale yellow crystal.
1H-NMR.delta. (DMSO-d6): 3.06 (2H, brs), 3.77 (2H, brs), 4.58 (2H,
brs), 5.38 (2H, s), 7.43 (1H, dd, J=7.6, 7.3 Hz), 7.76 (1H, dd,
J=8.4, 7.3 Hz), 7.82-8.00 (2H, m), 7.97 (1H, s), 8.04 (1H, d, J=8.4
Hz), 11.52 (1H, brs). MS (m/z): 471 (M-H)-.
Example 32
3-[4-hydroxy-3-(1-oxo-1,3-thiazolidine-3-carbonyl)-5-trifluoromethylbenzoy-
l]-1,1-dioxo-2,3-dihydro-1,3-benzothiazole
3-[4-hydroxy-3-(1,3-thiazolidine-3-carbonyl)-5-trifluoromethylbenzoyl]-1,-
1-dioxo-2,3-dihydro-1,3-benzothiazole (67 mg) was dissolved in
tetrahydrofuran (0.5 mL) and water (0.5 mL), and oxone (45 mg) was
added to the solution, and then the mixture was stirred at room
temperature for 1 hour. To the reaction solution, 1N hydrochloric
acid was added, and then the mixture was extracted with ethyl
acetate. The organic layer was washed with water and saturated
brine, and then dried over anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure and the obtained residue
was crystallized from n-hexane-chloroform to obtain the title
compound (46 mg) as a colorless crystal.
1H-NMR.delta. (DMSO-d6): 2.98-3.15 (2H, m), 3.94-4.06 (1H, m), 4.22
(1H, brs), 4.61 (2H, s), 5.32 (2H, s), 7.42 (1H, dd, J=7.6, 7.6
Hz), 7.74 (1H, dd, J=8.4, 7.6 Hz), 7.86 (1H, d, J=7.6 Hz), 7.88
(1H, d, J=2.2 Hz), 7.98 (1H, d, J=2.2 Hz), 8.01 (1H, d, J=8.4 Hz).
MS (m/z): 487 (M-H)-.
Example 33
1,1-dioxo-3-[3-(1,1-dioxo-1,3-thiazolidine-3-carbonyl)-4-hydroxy-5-trifluo-
romethylbenzoyl]-2,3-dihydro-1,3-benzothiazole
(a) Synthesis of
1,1-dioxo-3-[3-(1,1-dioxo-1,3-thiazolidine-3-carbonyl)-4-methoxy-5-triflu-
oromethylbenzoyl]-2,3-dihydro-1,3-benzothiazole
3-[4-methoxy-3-(1,3-thiazolidine-3-carbonyl)-5-trifluoromethylbenzoyl]-1,-
1-dioxo-2,3-dihydro-1,3-benzothiazole (300 mg) was dissolved in
chloroform (10 mL), and 70% metachloroperbenzoic acid (1.21 g) was
added to the solution. After stirring the mixture at room
temperature for 20 hours, 1N sodium hydroxide was added and the
mixture was extracted with ethyl acetate. The organic layer was
washed with 1N sodium hydroxide and saturated brine, and then dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure to obtain the title compound (266 mg) as a
colorless oily substance.
(b) Synthesis of
1,1-dioxo-3-[3-(1,1-dioxo-1,3-thiazolidine-3-carbonyl)-4-hydroxy-5-triflu-
oromethylbenzoyl]-2,3-dihydro-1,3-benzothiazole
1,1-dioxo-3-[3-(1,1-dioxo-1,3-thiazolidine-3-carbonyl)-4-methoxy-5-triflu-
oromethylbenzoyl]-2,3-dihydro-1,3-benzothiazole (260 mg) was
dissolved in N,N-dimethylformamide (2.5 mL), and lithium chloride
(200 mg) was added to the solution, and then the mixture was
stirred at 120.degree. C. for 1.5 hours. To the reaction solution,
1N hydrochloric acid was added, and then the mixture was extracted
with ethyl acetate. The organic layer was washed with water and
saturated brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure and the obtained
residue was crystallized from n-hexane-chloroform to obtain the
title compound (120 mg) as a pale yellow crystal.
1H-NMR.delta. (DMSO-d6): 3.50 (2H, t, J=6.8 Hz), 3.86-4.14 (2H, m),
4.64 (2H, s), 5.39 (2H, s), 7.44 (1H, dd, J=8.1, 7.6 Hz), 7.77 (1H,
dd, J=8.1, 7.6 Hz), 7.88 (1H, s), 7.91 (1H, d, J=8.1 Hz), 8.01 (1H,
s), 8.06 (1H, d, J=8.1 Hz). MS (m/z): 503 (M-H)-.
Example 34
3-(3-cyano-5-ethylsulfanyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-ben-
zothiazole
(a) Synthesis of methyl 3-cyano-4-methoxybenzoate
Methyl 3-cyano-4-hydroxybenzoate (1.00 g) was dissolved in
N,N-dimethylformamide (5 mL), and potassium carbonate (1.56 g) and
dimethylsulfuric acid (0.70 mL) were added to the solution, and
then the mixture was stirred at room temperature for 1 hour. After
the reaction solution was filtered, water was added and the
reaction mixture was extracted with ethyl acetate. The organic
layer was washed with saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure to obtain the title compound (923 mg) as a yellow
solid.
(b) Synthesis of 3-cyano-4-methoxybenzoic acid
Methyl 3-cyano-4-methoxybenzoate (879 mg) was dissolved in
tetrahydrofuran (8 mL) and water (4 mL), and lithium hydroxide
monohydrate (772 mg) was added to the solution, and then the
mixture was stirred at mom temperature for 1 hour. The organic
solvent was distilled off under reduced pressure and acidified with
2N hydrochloric acid, and then the precipitated crystal was
collected by filtration to obtain the title compound (754 mg) as a
colorless crystal.
1H-NMR.delta. (DMSO-d6): 4.00 (3H, s), 7.36 (1H, dd, J=6.6, 3.0
Hz), 8.18 (1H, d, J=3.0 Hz), 8.20 (1H, dd, 2.1 Hz), 13.17 (1H,
brs). MS (m/z): 176 (M-H)-.
(c) Synthesis of 3-cyano-4-methoxybenzoyl chloride
To 3-cyano-4-methoxybenzoic acid (1.78 g), toluene (20 mL),
N,N-dimethylformamide (3 droplets) and thionyl chloride (1.14 mL)
were added, and then the mixture was stirred at 60.degree. C. for
16 hours. The solvent was distilled off under reduced pressure and
the obtained residue was azeotroped with toluene and used for the
synthesis of (d).
(d) Synthesis of
3-(3-cyano-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol
(1.89 g) and 37% formalin (1.25 mL) in the same manner as in
Example 1 was dissolved in chloroform (20 mL), and triethylamine
(2.08 mL) and 3-cyano-4-methoxybenzoyl chloride were added to the
solution, and then the mixture was stirred at room temperature for
2 hours. The organic solvent was distilled off under reduced
pressure and extracted with ethyl acetate. The organic layer was
washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated
brine, and then dried over anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure and the obtained residue
was used for the synthesis of (e).
(e) Synthesis of
3-(3-cyano-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole
3-(3-cyano-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole was
dissolved in chloroform (50 mL), and 70% metachloroperbenzoic acid
(9.19 g) was added to the solution, and then the mixture was
stirred at room temperature for 20 hours and quenched with 10%
sodium thiosulfate. The solvent was distilled off under reduced
pressure and 1N sodium hydroxide was added, and then the mixture
was extracted with ethyl acetate. The organic layer was washed with
1N sodium hydroxide and saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure to obtain the title compound (2.30 g) as a pale
yellow solid.
(f) Synthesis of
3-(3-cyano-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole
3-(3-cyano-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole
(2.30 g) was dissolved in N,N-dimethylformamide (25 mL), and
lithium chloride (2.97 g) was added to the solution, and then the
mixture was stirred at 130.degree. C. for 12 hours. To the reaction
solution, 1N hydrochloric acid was added, and then the mixture was
extracted with ethyl acetate. The organic layer was washed with 1N
hydrochloric acid and saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure and the obtained residue was used for the
synthesis of (g).
(g) Synthesis of
3-(3-cyano-4-hydroxy-5-iodobenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazo-
le
3-(3-cyano-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole
was dissolved in dichloromethane (27 mL) and methanol (3 mL), and
N-iodosuccinimide (1.79 g) and trifluoromethanesulfonic acid (5
droplets) was added to the solution, and then the mixture was
stirred at room temperature for 15 hours. The solvent was distilled
off under reduced pressure and water was added, and then the
mixture was extracted with ethyl acetate. The organic layer was
washed with water and saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure and the obtained residue was crystallized from
n-hexane-ethyl acetate to obtain the title compound (1.30 g) as a
colorless crystal.
(h) Synthesis of
3-(3-cyano-5-ethylsulfanyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-be-
nzothiazole
3-(3-cyano-4-hydroxy-5-iodobenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazo-
le (500 mg) was dissolved in N,N-dimethylformamide (5 mL), and
2,2'-bipyridine (18 mg), zinc powder (149 mg), nickel bromide (25
mg) and diethyl disulfide (70 mg) were added to the solution, and
then the mixture was stirred at 110.degree. C. for 1 hour. After
the reaction solution was filtered, 1N hydrochloric acid was added
and the reaction mixture was extracted with ethyl acetate. The
organic layer was washed with saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure and the obtained residue was purified by silica
gel column chromatography (n-hexane:ethyl acetate=2:1) and then
crystallized from diethylether-ethyl acetate to obtain the title
compound (63 mg) as a colorless crystal.
1H-NMR.delta. (DMSO-d6): 1.22 (3H, t, J=7.3 Hz), 2.96 (2H, q, J=7.3
Hz), 5.35 (2H, s), 7.44 (1H, dd, J=7.6, 7.6 Hz), 7.77 (1H, ddd,
J=8.3, 3.6, 1.3 Hz), 7.79 (1H, d, J=1.8 Hz), 7.88-7.94 (2H, m),
8.07 (1H, d, J=8.3 Hz). MS (m/z): 373 (M-H)-.
Example 35
3-(3-cyano-4-hydroxy-5-isopropylsulfanylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-
-benzothiazole
3-(3-cyano-4-hydroxy-5-iodobenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazo-
le (1.03 mg) was dissolved in N,N-dimethylformamide (10 mL),
2,2'-bipyridine (37 mg), zinc powder (306 mg), nickel bromide (52
mg) and diisopropyl disulfide (176 mg) were added to the solution,
and then the mixture was stirred at 110.degree. C. for 1 hour.
After the reaction solution was filtered, 1N hydrochloric acid was
added and the reaction mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine, and then dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure and the obtained residue was purified by silica
gel column chromatography (n-hexane:ethyl acetate=2:1) to obtain
the title compound (153 mg) as a colorless crystal.
1H-NMR.delta. (DMSO-d6): 1.23 (6H, d, J=6.6 Hz), 3.46 (1H, sevent,
J=6.6 Hz), 5.35 (2H, s), 7.44 (1H, dd, J=7.4, 7.4 Hz), 7.76 (1H,
ddd, J=8.4, 7.4, 1.3 Hz), 7.90 (1H, d, J=2.1 Hz), 7.91 (1H, d,
J=7.4 Hz), 7.98 (1H, d, J=2.1 Hz), 8.04 (1H, d, J=8.4 Hz), 11.32
(1H, brs). MS (m/z): 387 (M-H)-.
Example 36
3-(3-cyano-4-hydroxy-5-trifluoromethoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3--
benzothiazole
(a) Synthesis of 1-methoxymethoxy-2-trifluoromethoxybenzene
2-trifluoromethoxyphenol (10.00 g) was dissolved in
N,N-dimethylformamide (50 mL), and potassium carbonate (15.52 g)
and chloromethyl methyl ether (4.70 mL) were added to the solution,
and then the mixture was stirred at room temperature for 1 hour.
Water was added to the reaction solution and then the mixture was
extracted with n-hexane. The organic layer was washed with
saturated brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure to obtain the
title compound (12.21 g) as a colorless oily substance.
(b) Synthesis of 2-hydroxy-3-trifluoromethoxybenzaldehyde
1-methoxymethoxy-2-trifluoromethoxybenzene (12.21 g) was dissolved
in tetrahydrofuran (120 mL), and a 1.59M
n-butyllithium-n-cyclohexane solution (40 mL) was added to the
solution at -60.degree. C. over 15 minutes under an argon gas flow,
and then the mixture was stirred for 1 hour. N,N-dimethylformamide
(6.30 mL) was added to the solution, and then the mixture was
stirred at room temperature for 30 minutes. 2N hydrochloric acid
(100 mL) was added to the solution, and then the mixture was
stirred at 60.degree. C. for 15 hours. The organic solvent was
distilled off under reduced pressure, and then the mixture was
extracted with ethyl acetate. The organic layer was washed with
saturated brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure to obtain the
title compound (10.38 g) as a colorless crystal.
(c) Synthesis of
5-bromo-2-hydroxy-3-trifluoromethoxybenzaldehyde
2-hydroxy-3-trifluoromethoxybenzaldehyde (10.38 g) was dissolved in
dichloromethane (100 mL), and N-bromosuccinimide (9.41 g) was added
to the solution, and then the mixture was stirred at room
temperature for 30 minutes. The solvent was distilled off under
reduced pressure and water was added, and then the mixture was
extracted with ethyl acetate. The organic layer was washed with 1N
hydrochloric acid, 10% sodium thiosulfate and saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure to obtain the title compound (14.27 g)
as a brown solid.
(d) Synthesis of
5-bromo-2-methoxy-3-trifluoromethoxybenzaldehyde
5-bromo-2-hydroxy-3-trifluoromethoxyaldehyde (5.00 g) was dissolved
in N,N-dimethylformamide (25 mL), and potassium carbonate (4.85 g)
and dimethylsulfuric acid (2.5 mL) was added to the solution, and
then the mixture was stirred at room temperature for 16 hours.
Water was added to the reaction solution and the reaction mixture
was extracted with ethyl acetate. The organic layer was washed with
water and saturated brine, and then dried over anhydrous sodium
sulfate. The solvent was distilled off under reduced pressure to
obtain the title compound (5.22 g) as a brown oily substance.
(e) Synthesis of
5-bromo-1-diethoxymethyl-2-methoxy-3-trifluoromethoxybenzene
5-bromo-2-methoxy-3-trifluoromethoxybenzaldehyde (5.22 g) was
dissolved in n-hexane (15 mL) and triethyl orthoformate (4.4 mL),
and Amberlyst-15 (522 mg) was added to the solution, and then the
mixture was refluxed for 3 hours. The reaction solution was
filtered, and then the solvent was distilled off under reduced
pressure to obtain the title compound (6.19 g) as a brown oily
substance.
(f) Synthesis of 3-formyl-4-methoxy-5-trifluoromethoxybenzoic
acid
To magnesium (403 mg), tetrahydrofuran (16 mL),
5-bromo-1-diethoxymethyl-2-methoxy-3-trifluoromethoxybenzene (6.19
g) and a 0.97M methylmagnesium bromide-tetrahydrofuran solution
(0.42 mL) were added to the solution, and then the mixture was
stirred at room temperature for 1 hour. The reaction solution was
cooled to 0.degree. C. and stirred for 45 minutes under a carbon
dioxide atmosphere. 4N hydrochloric acid (25 mL) was added and then
the mixture was stirred at room temperature for 30 minutes. The
organic solvent was distilled off under reduced pressure and the
mixture was extracted with diisopropylether. The organic layer was
extracted with 1N sodium hydroxide (100 mL) added thereto and the
aqueous layer was washed twice with diisopropylether. The aqueous
layer was acidified with 4N hydrochloric acid and then extracted
with ethyl acetate. The organic layer was washed with saturated
brine, and then dried over anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure to obtain the title
compound (4.22 g) as a brown solid.
(g) Synthesis of 3-cyano-4-methoxy-5-trifluoromethoxybenzoic
acid
3-formyl-4-methoxy-5-trifluoromethoxybenzoic acid (4.22 g) was
dissolved in formic acid (20 mL), and hydroxylamine hydrochloride
(1.22 g) was added to the solution, and then the mixture was
refluxed for 16 hours. The solvent was distilled off under reduced
pressure and 1N hydrochloric acid was added, and then the mixture
was extracted with ethyl acetate. The organic layer was washed with
saturated brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure to obtain the
title compound (3.97 g) as a brown solid.
1H-NMR.delta. (DMSO-d6): 4.17 (3H, s), 8.10-8.14 (1H, m), 828 (1H,
d, J=2.0 Hz), 13.73 (1H, brs). MS (m/z): 260 (M-H)-.
(h) Synthesis of 3-cyano-4-methoxy-5-trifluoromethoxybenzoyl
chloride
To 3-cyano-4-methoxy-5-trifluoromethoxybenzoic acid (500 mg),
toluene (10 mL), N,N-dimethylformamide (3 droplets) and thionyl
chloride (0.28 mL) were added, and then the mixture was stirred at
60.degree. C. for 6 hours. The solvent was distilled off under
reduced pressure and the obtained residue was azeotroped with
toluene and used for the synthesis of (i).
(i) Synthesis of
3-(3-cyano-4-methoxy-5-trifluoromethoxybenzoyl)-2,3-dihydro-1,3-benzothia-
zole
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol
(359 mg) and 37% formalin (0.24 mL) in the same manner as in
Example 1 was dissolved in chloroform (10 mL), and triethylamine
(0.80 mL) and 3-cyano-4-methoxy-5-trifluoromethoxybenzoyl chloride
were added to the solution, and then the mixture was stirred at
room temperature for 17 hours. The solvent was distilled off under
reduced pressure and water was added, and then the mixture was
extracted with ethyl acetate. The organic layer was washed with 1N
hydrochloric acid, 1N sodium hydroxide and saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure and the obtained residue was used for
the synthesis of (j).
(j) Synthesis of
3-(3-cyano-4-methoxy-5-trifluoromethoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-
-benzothiazole
3-(3-cyano-4-methoxy-5-trifluoromethoxybenzoyl)-2,3-dihydro-1,3-benzothia-
zole was dissolved in chloroform (15 mL), and 70%
metachloroperbenzoic acid (1.98 g) was added to the solution, and
then the mixture was stirred at room temperature for 6 hours and
quenched with 10% sodium thio sulfate. The solvent was distilled
off under reduced pressure and 1N sodium hydroxide was added, and
then the mixture was extracted with ethyl acetate. The organic
layer was washed with 1N sodium hydroxide and saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure to obtain the title compound (631 mg) as
a pale yellow solid.
(k) Synthesis of
3-(3-cyano-4-hydroxy-5-trifluoromethoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-
-benzothiazole
3-(3-cyano-4-methoxy-5-trifluoromethoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-
-benzothiazole (300 mg) was dissolved in N,N-dimethylformamide (4
mL), and lithium chloride (309 mg) was added to the solution, and
then the mixture was stirred at 100.degree. C. for 1 hour. To the
reaction solution, 1N hydrochloric acid was added, and then the
mixture was extracted with ethyl acetate. The organic layer was
washed with 1N hydrochloric acid and saturated brine, and then
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure and the obtained residue was crystallized
from n-hexane-ethyl acetate to obtain the title compound (184 mg)
as a colorless crystal.
1H-NMR.delta. (DMSO-d6): 5.37 (2H, s), 7.42 (1H, ddd, J=7.3, 7.3,
0.7 Hz), 7.77 (1H, ddd, J=8.4, 7.3, 1.3 Hz), 7.88-7.96 (2H, m),
8.04-8.11 (2H, m). MS (m/z): 397 (M-H)-.
Example 37
3-(3-chloro-4-hydroxy-5-trifluoromethoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-
-benzothiazole
(a) Synthesis of acetic acid-2-trifluoromethoxyphenyl ester
2-trifluoromethoxyphenol (10.00 g) was dissolved in chloroform (30
mL), and triethylamine (6.11 mL) and acetic anhydride (6.37 mL) was
added to the solution, and then the mixture was stirred at room
temperature for 2 hours. To the reaction solution, 10% potassium
carbonate was added, and then the mixture was extracted with
chloroform. The organic layer was washed with an aqueous 5% citric
acid solution and saturated brine, and then dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure to obtain the title compound (11.39 g) as a colorless oily
substance.
(b) Synthesis of 1-(4-hydroxy-3-trifluoromethoxyphenyl)ethanone
An acetic acid-2-trifluoromethoxyphenyl ester (11.39 g) was
dissolved in trifluoromethanesulfonic acid (10 mL), and then the
solution was stirred at room temperature for 2.5 hours. The
reaction solution was poured into ice water and the reaction
mixture was extracted with ethyl acetate. The organic layer was
washed with water and saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure and the obtained residue was purified by silica
gel column chromatography (n-hexane:ethyl acetate=3:1) to obtain
the title compound (4.55 g) as a colorless crystal.
(c) Synthesis of
1-(4-methoxymethoxy-3-trifluoromethoxyphenyl)ethanone
1-(4-hydroxy-3-trifluoromethoxyphenyl)ethanone (1.55 g) was
dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate
(1.46 g) and chloromethyl methyl ether (0.64 mL) were added to the
solution, and then the mixture was stirred at room temperature for
1 hour. Water was added to the reaction solution and the reaction
mixture was extracted with ethyl acetate. The organic layer was
washed with water and saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure to obtain the title compound (1.54 g) as a
colorless oily substance.
(d) Synthesis of methyl
4-methoxymethoxy-3-trifluoromethoxybenzoate
1-(4-methoxymethoxy-3-trifluoromethoxyphenyl)ethanone (540 mg) was
dissolved in methanol (30 mL), and sodium methoxide (1.10 g) and
N-bromosuccinimide (1.09 g) were added to the solution, and then
the mixture was stirred at room temperature for 30 minutes. Water
was added to the reaction solution and the reaction mixture was
extracted with ethyl acetate. The organic layer was washed with
saturated brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure to obtain the
title compound (590 mg) as a yellow crystal.
(e) Synthesis of methyl 4-hydroxy-3-trifluoromethoxybenzoate
Methyl 4-methoxymethoxy-3-trifluoromethoxybenzoate (590 mg) was
dissolved in chloroform (10 mL), and trifluoroacetic acid (5 mL)
was added to the solution, and then the mixture was stirred at room
temperature for 1 hour. Water was added to the solution, and then
the mixture was extracted with chloroform. The organic layer was
washed with saturated brine, and then dried over anhydrous sodium
sulfate. The solvent was distilled off under reduced pressure and
the obtained residue was washed with n-hexane to obtain the title
compound (346 mg) as a colorless crystal.
(f) Synthesis of methyl
3-chloro-4-hydroxy-5-trifluoromethoxybenzoate
Methyl 4-hydroxy-3-trifluoromethoxybenzoate (2.05 g) was dissolved
in chloroform (20 mL) and methanol (3 mL), and N-chlorosuccinimide
(1.39 g) and trifluoromethanesulfonic acid (0.05 mL) were added to
the solution, and then the mixture was stirred at 50.degree. C. for
19 hours. The solvent was distilled off under reduced pressure and
1N hydrochloric acid was added, and then the mixture was extracted
with ethyl acetate. The organic layer was washed with water and
saturated brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure to obtain the
title compound (2.64 g) as a yellow solid.
(g) Synthesis of methyl
3-chloro-4-methoxy-5-trifluoromethoxybenzoate
Methyl 3-chloro-4-hydroxy-5-trifluoromethoxybenzoate (2.64 g) was
dissolved in N,N-dimethylformamide (15 mL), and potassium carbonate
(3.60 g) and dimethylsulfuric acid (1.64 mL) were added to the
solution, and then the mixture was stirred at room temperature for
1 hour. Water was added to the reaction solution and the reaction
mixture was extracted with ethyl acetate. The organic layer was
washed with water and saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure and the obtained residue was purified by silica
gel column chromatography (n-hexane:ethyl acetate=9:1) to obtain
the title compound (1.70 g) as a colorless oily substance.
(h) Synthesis of 3-chloro-4-methoxy-5-trifluoromethoxybenzoic
acid
Methyl 3-chloro-4-methoxy-5-trifluoromethoxybenzoate (1.70 g) was
dissolved in tetrahydrofuran (12 mL) and water (6 mL), and lithium
hydroxide monohydrate (1.00 g) was added to the solution, and the
mixture was stirred at room temperature for 2 hours. The solvent
was distilled off under reduced pressure and 1N hydrochloric acid
was added, and then the mixture was extracted with ethyl acetate.
The organic layer was washed with water and saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure to obtain the title compound (1.51 g) as
a colorless crystal.
1H-NMR.delta. (CDCl3): 4.04 (3H, s), 7.93 (1H, s), 8.10 (1H, d,
J=1.9 Hz). MS (m/z): 269 (M-H)-.
(i) Synthesis of 3-chloro-4-methoxy-5-trifluoromethoxybenzoyl
chloride
To 3-chloro-4-methoxy-5-trifluoromethoxybenzoic acid (401 mg),
toluene (4 mL), N,N-dimethylformamide (1 droplet) and thionyl
chloride (0.13 mL) were added, and then the mixture was stirred at
60.degree. C. for 13 hours. The solvent was distilled off under
reduced pressure and then azeotroped with toluene to obtain the
title compound (436 mg) as a brown oily substance.
(j) Synthesis of
3-(3-chloro-4-methoxy-5-trifluoromethoxybenzoyl)-2,3-dihydro-1,3-benzothi-
azole
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol
(278 mg) and 37% formalin (0.18 mL) in the same manner as in
Example 1 was dissolved in dichloromethane (6.5 mL), and
diisopropylethylamine (0.50 mL) and
3-chloro-4-methoxy-5-trifluoromethoxybenzoyl chloride (436 mg) were
added to the solution, and then the mixture was stirred at room
temperature for 1 hour. The solvent was distilled off under reduced
pressure and water was added, and then the mixture was extracted
with ethyl acetate. The organic layer was washed with 1N
hydrochloric acid, 1N sodium hydroxide and saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure and the obtained residue was used for
the synthesis of (k).
(k) Synthesis of
3-(3-chloro-4-methoxy-5-trifluoromethoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,-
3-benzothiazole
3-(3-chloro-4-methoxy-5-trifluoromethoxybenzoyl)-2,3-dihydro-1,3-benzothi-
azole was dissolved in chloroform (10 mL), and 70%
metachloroperbenzoic acid (2.57 g) was added to the solution, and
then the mixture was stirred at room temperature for 22 hours. 1N
sodium hydroxide was added, and then the mixture was extracted with
ethyl acetate. The organic layer was washed with 1N sodium
hydroxide and saturated brine, and then dried over anhydrous sodium
sulfate. The solvent was distilled off under reduced pressure and
the obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=4:1) to obtain the title
compound (420 mg) as a colorless oily substance.
(l) Synthesis of
3-(3-chloro-4-hydroxy-5-trifluoromethoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,-
3-benzothiazole
3-(3-chloro-4-methoxy-5-trifluoromethoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,-
3-benzothiazole (420 mg) was dissolved in N,N-dimethylformamide (5
mL), and lithium chloride (421 mg) was added to the solution, and
then the mixture was stirred at 120.degree. C. for 14 hours. To the
reaction solution, 1N hydrochloric acid was added, and then the
mixture was extracted with ethyl acetate. The organic layer was
washed with 1N hydrochloric acid and saturated brine, and then
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure and the obtained residue was crystallized
from n-hexane-ethyl acetate to obtain the title compound (182 mg)
as a colorless crystal.
1H-NMR.delta. (DMSO-d6): 5.36 (2H, s), 7.44 (1H, dd, J=7.6, 7.0
Hz), 7.67 (1H, brs), 7.76 (1H, dd, J=8.1, 7.6 Hz), 7.82 (1H, d,
J=2.2 Hz), 7.91 (1H, d, J=7.0 Hz), 8.03 (1H, d, J=8.1 Hz), 11.52
(1H, brs). MS (m/z): 406 (M-H)-.
Example 38
3-(3-cyano-4-hydroxy-5-trifluoromethylbenzoyl)-1,1-dioxo-5-trifluoromethyl-
-2,3-dihydro-1,3-benzothiazole
(a) Synthesis of
5-trifluoromethyl-2,3-dihydro-1,3-benzothiazole
37% formalin (0.22 mL) was diluted with water (6 mL), and
diethylether (6 mL), triethylamine (0.37 mL) and
2-amino-4-trifluoromethylbenzenethiol hydrochloride (611 mg) were
added to the solution, and then the mixture was stirred at room
temperature for 30 minutes. The organic layer was separated and the
aqueous layer was extracted with diethylether. The organic layers
were combined, washed with saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure and the obtained residue was used for the
synthesis of (b).
(b) Synthesis of
3-(3-cyano-4-methoxy-5-trifluoromethylbenzoyl)-5-trifluoromethyl-2,3-dihy-
dro-1,3-benzothiazole
5-trifluoromethyl-2,3-dihydro-1,3-benzothiazole was dissolved in
dichloromethane (5 mL), and triethylamine (0.56 mL) and
3-cyano-4-methoxy-5-trifluoromethylbenzoyl chloride (839 mg) were
added to the solution, and then the mixture was stirred at room
temperature for 1.5 hours. Water was added and the mixture was
extracted with ethyl acetate. The organic layer was washed with 1N
hydrochloric acid, 1N sodium hydroxide and saturated brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure and the obtained residue was purified by
silica gel column chromatography (n-hexane:ethyl acetate=8:1) to
obtain the title compound (479 mg) as a pale yellow amorphous
product.
(c) Synthesis of
3-(3-cyano-4-methoxy-5-trifluoromethylbenzoyl)-1,1-dioxo-5-trifluoromethy-
l-2,3-dihydro-1,3-benzothiazole
3-(3-cyano-4-methoxy-5-trifluoromethylbenzoyl)-5-trifluoromethyl-2,3-dihy-
dro-1,3-benzothiazole (520 mg) was dissolved in chloroform (8 mL),
and 70% metachloroperbenzoic acid (2.37 g) was added to the
solution at 0.degree. C. After stirring the mixture at room
temperature for 40 hours, 1N sodium hydroxide was added, and then
the precipitated crystal was collected by filtration and washed
with 1N sodium hydroxide and water. Furthermore, the filtrate was
extracted with ethyl acetate, and the organic layer was washed with
1N sodium hydroxide and saturated brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure and the obtained product was combined with the
crystal collected by filtration, and then the mixture was washed
with a mixture of n-hexane and ethyl acetate in a mixing ratio of
1:1 to obtain the title compound (459 mg) as a colorless
crystal.
(d) Synthesis of
3-(3-cyano-4-hydroxy-5-trifluoromethylbenzoyl)-1,1-dioxo-5-trifluoromethy-
l-2,3-dihydro-1,3-benzothiazole
3-(3-cyano-4-methoxy-5-trifluoromethylbenzoyl)-1,1-dioxo-5-trifluoromethy-
l-2,3-dihydro-1,3-benzothiazole (459 mg) was dissolved in
N,N-dimethylformamide (4.5 mL), and lithium chloride (169 mg) was
added to the solution, and then the mixture was stirred at
70.degree. C. for 1 hour. To the reaction solution, 1N hydrochloric
acid was added, and then the mixture was extracted with ethyl
acetate. The organic layer was washed with 1N hydrochloric acid and
saturated brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure and the obtained
residue was crystallized from n-hexane-chloroform to obtain the
title compound (411 mg) as a colorless crystal.
1H-NMR.delta. (DMSO-d6): 5.47 (2H, s), 7.81 (1H, d, J=8.1 Hz), 8.10
(1H, s), 8.21 (1H, d, J=8.1 Hz), 8.28 (1H, s), 8.43 (1H, s). MS
(m/z): 449 (M-H)-.
Example 39
3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-5-trifluoromethyl-2,3-dihydro--
1,3-benzothiazole
(a) Synthesis of
3-(3,5-dichloro-4-methoxybenzoyl)-5-trifluoromethyl-2,3-dihydro-1,3-benzo-
thiazole
2-amino-4-trifluoromethylbenzenethiol hydrochloride (502 mg), and
5-trifluoromethyl-2,3-dihydro-1,3-benzothiazole synthesized from
37% formalin (0.18 mL) and triethylamine (0.30 mL) in the same
manner as in Example 38 were dissolved in dichloromethane (5 mL),
and triethylamine (0.30 mL) and 3,5-dichloro-4-methoxybenzoyl
chloride (354 mg) were added to the solution, and then the mixture
was stirred at room temperature for 2 hours. Water was added and
the mixture was extracted with ethyl acetate. The organic layer was
washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated
brine, and then dried over anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure and the obtained residue
was purified by silica gel column chromatography (n-hexane:ethyl
acetate=8:1) to obtain the title compound (223 mg) as a colorless
oily substance.
(b) Synthesis of
3-(3,5-dichloro-4-methoxybenzoyl)-1,1-dioxo-5-trifluoromethyl-2,3-dihydro-
-1,3-benzothiazole
3-(3,5-dichloro-4-methoxybenzoyl)-5-trifluoromethyl-2,3-dihydro-1,3-benzo-
thiazole (223 mg) was dissolved in chloroform (5 mL), and 70%
metachloroperbenzoic acid (805 mg) was added to the solution at
0.degree. C. After stirring the mixture at room temperature for 20
hours, 1N sodium hydroxide was added, and then the mixture was
extracted with ethyl acetate. The organic layer was washed with 1N
sodium hydroxide and saturated brine, and then dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure to obtain the title compound (211 mg) as a pale yellow
crystal.
(c) Synthesis of
3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-5-trifluoromethyl-2,3-dihydro-
-1,3-benzothiazole
3-(3,5-dichloro-4-methoxybenzoyl)-1,1-dioxo-5-trifluoromethyl-2,3-dihydro-
-1,3-benzothiazole (209 mg) was dissolved in N,N-dimethylformamide
(2 mL), lithium chloride (106 mg) was added to the solution, and
then the mixture was stirred at 120.degree. C. for 2 hours. To the
reaction solution, 1N hydrochloric acid was added, and then the
mixture was extracted with ethyl acetate. The organic layer was
washed with 1N hydrochloric acid and saturated brine, and then
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure and the obtained residue was crystallized
from n-hexane-chloroform to obtain the title compound (167 mg) as a
pale yellow crystal.
1H-NMR.delta. (DMSO-d6): 5.46 (2H, s), 7.76 (2H, s), 7.80 (1H, d,
J=8.1 Hz), 8.20 (1H, d, J=8.1 Hz), 8.41 (1H, s), 11.11 (1H, brs).
MS (m/z): 424 (M-H)-, 426 (M+2-H)-.
Example 40
3-(3-chloro-4-hydroxy-5-trifluoromethylbenzoyl)-5 or
6-hydroxy-1,1-dioxo-2,3-dihydro-1,3-benzothiazole
3-(3-chloro-4-hydroxy-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-
-benzothiazole (941 mg) obtained in Example 18 was suspended in
15.7 mL of a 0.5% methyl cellulose solution (0.5% MC) and the
suspension was administered to eight male Wistar/ST rats in each
amount of 1.8 mL and urine was collected for 6.5 hours immediately
after administration. The obtained urine (28 mL) was acidified with
hydrochloric acid and then extracted with ethyl acetate. The
obtained organic layer was washed with brine, and d then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure and the obtained residue was purified by silica
gel column chromatography (n-hexane:ethyl acetate=1:1) and then
crystallized from n-hexane:ethyl acetate to obtain the title
compound (36 mg).
1H-NMR.delta. (DMSO-d6): 5.34 (2H, s), 7.09 (1H, d, Hz), 7.15 (1H
dd, J=9.0, 2.6 Hz), 7.82 (1H, d, J=1.9 Hz), 7.90 (1H, d, J=9.0 Hz),
8.02 (1H, d, J=1.9 Hz), 10.34 (1H, s), 11.38 (1H, brs). MS (m/z):
406 (M-H)-, 408 (M+2-H)-.
In the following Table 1, R1, R2, R3 and X in the above respective
Examples are listed with respect to the compound represented by the
general formula (1).
TABLE-US-00001 TABLE 1 Examples R.sup.1 R.sup.2 R.sup.3 X Example 1
Cl Cl -- SO.sub.2 Example 2 Cl Cl -- S Example 3 Cl Cl -- SO
Example 4 CF.sub.3 CN -- SO.sub.2 Example 5 CF.sub.3 CN -- S
Example 6 CF.sub.3 CN -- SO Example 7 Cl CN -- SO.sub.2 Example 8
Cl CN -- S Example 9 tBu CN -- SO.sub.2 Example 10 iPr CN --
SO.sub.2 Example 11 cBu CN -- SO.sub.2 Example 12 Et CN -- SO.sub.2
Example 13 cPr CN -- SO.sub.2 Example 14 C.ident.CH CN -- SO.sub.2
Example 15 S--Me CN -- SO.sub.2 Example 16 SO.sub.2Me CN --
SO.sub.2 Example 17 SOMe CN -- SO.sub.2 Example 18 CF.sub.3 Cl --
SO.sub.2 Example 19 F Cl -- SO.sub.2 Example 20 F F -- SO.sub.2
Example 21 S--Me Cl -- SO.sub.2 Example 22 SO.sub.2Me Cl --
SO.sub.2 Example 23 SOMe Cl -- SO.sub.2 Example 24 SO.sub.2Me
CF.sub.3 -- SO.sub.2 Example 25 SO.sub.2Me tBu -- SO.sub.2 Example
26 CF.sub.3 OMe -- SO.sub.2 Example 27 CF.sub.3 CONMe.sub.2 --
SO.sub.2 Example 28 CF.sub.3 -- -- SO.sub.2 Example 29 OMe Cl --
SO.sub.2 Example 30 CF.sub.3 ##STR00008## -- SO.sub.2 Example 31
CF.sub.3 ##STR00009## -- SO.sub.2 Example 32 CF.sub.3 ##STR00010##
-- SO.sub.2 Example 33 CF.sub.3 ##STR00011## -- SO.sub.2 Example 34
S--Et CN -- SO.sub.2 Example 35 S--iPr CN -- SO.sub.2 Example 36
OCF.sub.3 CN -- SO.sub.2 Example 37 OCF.sub.3 Cl -- SO.sub.2
Example 38 CF.sub.3 CN 5-CF.sub.3 SO.sub.2 Example 39 Cl Cl
5-CF.sub.3 SO.sub.2 Example 40 CF.sub.3 Cl 5 or 6-OH SO.sub.2
Test Example 1
Uricosuric Action in Rat Pyrazinamide Model
Pyrazinamide suspended in a 0.5% methyl cellulose solution (0.5%
MC) was orally administered to 7- and 8-week-old male Wistar/ST
rats (4 rats per group) fasted for about 16 hours in a dose of 400
mg/kg. After 30 minutes, a test substance suspended in 0.5% MC was
orally administered in a dose of 30 mg/kg, and urine was collected
for 1 hour in a range from 2 to 3 hours after administration. At
the beginning of collection of urine and after completion of
collection of urine, rats were forced to urinate by pressing the
abdomen of the rat. The concentration of uric acid and that of
creatinine in urine were measured by a kit, and a ratio of the
concentration of uric acid to that of creatinine was used as an
indicator of a uricosuric action. The action of each test substance
was expressed by percentage to control.
Test Example 2
Concentration of Unchanged Compound in Urine in Rat
A test substance suspended in 0.5% MC was orally administered to
two male Wistar/ST rats fasted for about 16 hours in a dose of 3
mg/kg. Immediately after administration, urine was collected for 4
hours. After completion of collection of urine, urine remaining in
the bladder was completely excreted by pressing the abdomen of the
rat. The concentration of an unchanged compound in urine was
measured by HPLC and expressed by a molar concentration
(.mu.M).
The above test results are shown in Table 2 below.
TABLE-US-00002 TABLE 2 Uricosuric action (control = Concentration
of unchanged Examples 100) compound in urine (.mu.M) Example 1 169
9.8 Example 4 201 51.8 Example 5 136 1.1 Example 7 178 125 Example
12 187 15.8 Example 13 172 3.9 Example 14 164 119 Example 15 204
68.6 Example 18 202 1 Example 19 129 55.2 Example 21 120 1.9
Example 27 146 30.6 Example 34 208 23.5 Example 35 140 1.5 Example
38 180 16.4 Benzbromarone 114 0 Probenecid 111 0 171 (100
mg/kg)
As described above, a novel phenol derivative represented by the
general formula (1), a pharmaceutically acceptable salt thereof,
and a hydrate thereof and a solvate thereof exhibit a uricosuric
action of 20% to 108%, and also have excellent drug effectiveness
as compared with an existing drug which exhibits a uricosuric
action of 11% to 14%. A novel phenol derivative represented by the
general formula (1), a pharmaceutically acceptable salt thereof,
and a hydrate thereof and a solvate thereof are excellent in that
an unchanged compound exert drug effectiveness, as compared with an
existing drug in which excretion of an unchanged compound in urine
is not recognized, since an unchanged compound is clearly excreted
in urine. Accordingly, a novel phenol derivative represented by the
general formula (1), a pharmaceutically acceptable salt thereof,
and a hydrate thereof and a solvate thereof exhibit high
concentration of an unchanged compound in urine, and also have
excellent uricosuric action and are excellent in safety, and are
therefore useful as a pharmaceutical for the acceleration of
excretion of uric acid; a pharmaceutical for the reduction of the
amount of uric acid and/or concentration of uric acid in blood
and/or in tissue; a pharmaceutical for use in the prevention and/or
treatment of a disease associated with uric acid in blood and/or in
tissue; a pharmaceutical for use in the prevention and/or treatment
of hyperuricaemia; and a pharmaceutical for use in the prevention
and/or treatment of a disease associated with hyperuricaemia and/or
a disease accompanied by hyperuricaemia.
Formulation Example
Tablets
TABLE-US-00003 Compound of Example 1 5 mg Lactose 70 mg Corn starch
21 mg Hydroxypropyl cellulose 3 mg Magnesium stearate 1 mg Total
100 mg
After weighing the above components in a ratio according to the
formulation, a powder for compression is produced by a wet
granulation method. To obtain tablets, this powder was compressed
so as to contain 5 mg of the compound of Example 1 in one
tablet.
The compounds of the present invention exhibit high concentration
of an unchanged compound in urine, and also have excellent
uricosuric action and are excellent in safety, and are therefore
useful as a pharmaceutical for the acceleration of excretion of
uric acid; a pharmaceutical for the reduction of the amount of uric
acid and/or concentration of uric acid in blood and/or in tissue; a
pharmaceutical for use in the prevention and/or treatment of a
disease associated with uric acid in blood and/or in tissue; a
pharmaceutical for use in the prevention and/or treatment of
hyperuricaemia; and a pharmaceutical for use in the prevention
and/or treatment of a disease associated with hyperuricaemia and/or
a disease accompanied by hyperuricaemia.
* * * * *
References